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Numerous experimental data have documented the oncostatic properties of melatonin. In addition to its potential direct antitumor activity, melatonin has proved to modulate the effects of cancer chemotherapy, by enhancing its therapeutic efficacy and reducing its toxicity. The increase in chemotherapeutic efficacy by melatonin may depend on two main mechanisms, namely prevention of chemotherapy-induced lymphocyte damage and its antioxidant effect, which has been proved to amplify cytotoxic actions of the chemotherapeutic agents against cancer cells. However, the clinical results available at present with melatonin and chemotherapy in the treatment of human neoplasms are generally limited to the evaluation of 1-year survival in patients with very advanced disease. Thus, the present study was performed to assess the 5-year survival results in metastatic non-small cell lung cancer patients obtained with a chemotherapeutic regimen consisting of cisplatin and etoposide, with or without the concomitant administration of melatonin (20 mg/day orally in the evening). The study included 100 consecutive patients who were randomized to receive chemotherapy alone or chemotherapy and melatonin. Both the overall tumor regression rate and the 5-year survival results were significantly higher in patients concomitantly treated with melatonin. In particular, no patient treated with chemotherapy alone was alive after 2 years, whereas a 5-year survival was achieved in three of 49 (6%) patients treated with chemotherapy and melatonin. Moreover, chemotherapy was better tolerated in patients treated with melatonin. This study confirms, in a considerable number of patients and for a long follow-up period, the possibility to improve the efficacy of chemotherapy in terms of both survival and quality of life by a concomitant administration of melatonin. This suggests a new biochemotherapeutic strategy in the treatment of human neoplasms.

Recent studies suggest that the pineal hormone melatonin may reduce chemotherapy-induced immune and bone marrow damage. In addition, melatonin may exert potential oncostatic effects either by stimulating host anticancer immune defenses or by inhibiting tumor growth factor production. On this basis, we have performed a randomized study of chemotherapy alone vs. chemotherapy plus melatonin in advanced non-small cell lung cancer patients (NSCLC) with poor clinical status. The study included 70 consecutive advanced NSCLC patients who were randomized to receive chemotherapy alone with cisplatin (20 mg/m2/day i.v. for 3 days) and etoposide (100 mg/m2/day i.v. for 3 days) or chemotherapy plus melatonin (20 mg/day orally in the evening). Cycles were repeated at 21-day intervals. Clinical response and toxicity were evaluated according to World Health Organization criteria. A complete response (CR) was achieved in 1/34 patients concomitantly treated with melatonin and in none of the patients receiving chemotherapy alone. Partial response (PR) occurred in 10/34 and in 6/36 patients treated with or without melatonin, respectively. Thus, the tumor response rate was higher in patients receiving melatonin (11/34 vs. 6/35), without, however, statistically significant differences. The percent of 1-year survival was significantly higher in patients treated with melatonin plus chemotherapy than in those who received chemotherapy alone (15/34 vs. 7/36, P < 0.05). Finally, chemotherapy was well tolerated in patients receiving melatonin, and in particular the frequency of myelosuppression, neuropathy, and cachexia was significantly lower in the melatonin group. This study shows that the concomitant administration of melatonin may improve the efficacy of chemotherapy, mainly in terms of survival time, and reduce chemotherapeutic toxicity in advanced NSCLC, at least in patients in poor clinical condition.

Polychemotherapy represents the only standard medical therapy of metastatic soft tissue sarcomas (STS), whereas the recent biotherapies with cytokines, such as interleukin-2 (IL-2), seem not to have a relevant therapeutic role. The pineal hormone melatonin (MLT), whose immunomodulating activity is well known, would seem to exert a direct cytostatic action on STS cell proliferation. Moreover, MLT has been proven to amplify IL-2 efficacy. On this basis, a pilot phase II study with low-dose IL-2 plus MLT has been performed in untreatable metastatic STS patients. The study included 13 evaluable metastatic STS patients with poor PS, who progressed on at least one previous polychemotherapeutic line. IL-2 was injected subcutaneously at 3 million IU/day for 6 days/week for 4 weeks and MLT was given orally at 40 mg/day in the evening. A partial response was achieved in one patient with leiomyosarcoma. Eight other patients had a stable disease (SD) whereas the remaining 4 patients progressed. A survival longer than 1 year was achieved in 6/13 patients and the percent of 1-year survival was significantly higher in patients with response or SD than in the progressed ones (6/9 vs 0/4). Mean increases in lymphocyte and eosinophil numbers were significantly higher in patients with response or SD than in the progressed ones. These preliminary results would suggest that immunotherapy with low-dose IL-2 plus MLT may have some impact at least on the survival time of untreatable metastatic STS patients with poor clinical conditions.

In an attempt to further understand the biological significance of soluble IL-2 receptors (sIL-2R) in solid tumors, we have evaluated 160 cancer patients (breast: 40; lung: 66; colon: 18; stomach: 22; uterine cervix: 14) and 58 healthy subjects, as controls. Serum mean levels of sIL-2R, measured with an enzyme immunoassay, were significantly higher in cancer patients than in controls. Metastatic cancer patients showed significantly higher values than the non-metastatic ones; this difference was significant in all tumor histotypes, except small cell lung carcinoma. Moreover, in 15 patients in whom sIL-2R were evaluated either before or after radical surgery, a significant surgery-induced increase in sIL-R mean values was seen. Finally, the chemotherapy-induced rise in sIL-2R appeared to be associated with a lack of clinical response. These results seem to suggest that sIL-2R may be a marker of host biological response in patients with solid tumors, the significance of which needs further investigation.

According to recent advances in psychoneuroimmunology concerning the neurobiochemistry of emotions, the pshychological status of cancer patients should be investigated in relation to the function of the psychoneurodocrine system, in an attempt to put into evidence possible cancer progression-related alterations, particularly those involving the dopaminergic pathways, which play a fundamental role in the perception of pleasure. In fact, the decreased capacity of feeling pleasure is one of the most frequent psychic symptoms occurring in cancer patients. Rorschach's test has been proven to be an appropriate psychological tool to investigate psychic condition including sexual and spiritual profiles. On this basis, a study was planned to evaluate if a relation exists between psychological response to Rorschach's test and immunoneuroendocrine status of cancer patients. The immune status was investigated by measuring lymphocyte subsets and serum levels of IL-2 and IL-10. The neuroendocrine status was analyzed by evaluating the endocrine response of PRL, GH and cortisol to an oral administration of apomorphine (0.01 mg/kg b.w.), a dopaminergic agent able to explore dopaminergic sensitivity. The study included 40 cancer patients (breast cancer: 15; colorectal cancer: 14; lung cancer: 11), 21 of whom showed distant organ metastases. Rorschach's test demonstrated a simultaneous suppression of sexual and spiritual profiles in 31/40 (78%) patients, without significant differences in relation to either tumor histotype or disease state. A normal decline in PRL levels and a normal increase in those of GH and cortisol was observed in 29/40 (73%), 5/40 (13%) and 9/40 (23%) patients. The percent of normal responses of PRL, GH and cortisol was higher in patients with normal than in those with altered response to Rorschach's test, even though only the difference in PRL and cortisol response was statistically significant. Patients with normal sexual and spiritual expression at Rorschach's test showed a significantly higher number of total lymphocytes, T lymphocytes, T helper lymphocytes and NK cells with respect to the patients with altered psychological response, whereas no difference was found in T cytotoxic lymphocyte mean number. IL-2 and IL-10 mean serum concentrations were lower and higher, respectively, in patients with altered than in those with normal response to Rorschach's test, even though only the difference in IL-10 values was statitistically significant. This preliminary study, carried out to analyze the psychological status of cancer patients in relation to neuroendocrine and immune conditions, would suggest that neoplastic disease is characterized by a simultaneous suppression of sexual and spiritual profiles, and that this is associated with neuroendocrine alterations and immunosuppression.

In addition to the occurrence of pain, the evidence of a diminished capacity to feel pleasure is one of the most common cancer-related symptoms. Recent advances in psychoneuroendocrinological knowledge has shown that the perception of pleasure is mainly mediated by the dopaminergic pathways in the brain. Moreover, it has also been demonstrated that the brain dopaminergic sensitivity may be clinically explored by evaluating the endocrine response to the administration of dopaminergic agents, such as apomorphine, which consists of a decline in PRL concentrations and an increase in GH and cortisol levels. The present study was performed to evaluate dopaminergic sensitivity by the administration of apomorphine in cancer patients in an attempt to document possible cancer-related neuroendocrine anomalies, which could explain the psychological status of the patients. The study included 24 cancer patients (breast cancer: 12; colorectal cancer: 7; non-small cell lung cancer: 5), 12 of whom showed distant organ metastases. Apomorphine was given orally at 0.01 mg/kg b.w., by collecting venous blood samples before and after 20 and 60 minutes. A normal decline in PRL levels was seen in both non-metastatic and metastatic cancer patients. No cortisol increase in response to apomorphine was achieved and the lack of cortisol response was particularly evident in metastatic patients. No GH rise occurred in either metastatic or non-metastatic cancer patients. Finally, no significant difference in the endocrine response to apomorphine was seen in relation to the histotype of tumor. The results of this study show that the neoplastic disease is characterized by neurochemical alterations involving pleasure-related dopaminergic pathways, which are more evident in the metastatic disease, without particular differences in relation to tumor histotype. Therefore, the psychological condition of cancer patients would not depend only on psychological factors, but it could be due at least in part to cancer-related neuroendocrine alterations involving the dopaminergic system.

Numerous experimental data have documented the oncostatic properties of melatonin. In addition to its potential direct antitumor activity, melatonin has proved to modulate the effects of cancer chemotherapy, by enhancing its therapeutic efficacy and reducing its toxicity. The increase in chemotherapeutic efficacy by melatonin may depend on two main mechanisms, namely prevention of chemotherapy-induced lymphocyte damage and its antioxidant effect, which has been proved to amplify cytotoxic actions of the chemotherapeutic agents against cancer cells. However, the clinical results available at present with melatonin and chemotherapy in the treatment of human neoplasms are generally limited to the evaluation of 1-year survival in patients with very advanced disease. Thus, the present study was performed to assess the 5-year survival results in metastatic non-small cell lung cancer patients obtained with a chemotherapeutic regimen consisting of cisplatin and etoposide, with or without the concomitant administration of melatonin (20 mg/day orally in the evening). The study included 100 consecutive patients who were randomized to receive chemotherapy alone or chemotherapy and melatonin. Both the overall tumor regression rate and the 5-year survival results were significantly higher in patients concomitantly treated with melatonin. In particular, no patient treated with chemotherapy alone was alive after 2 years, whereas a 5-year survival was achieved in three of 49 (6%) patients treated with chemotherapy and melatonin. Moreover, chemotherapy was better tolerated in patients treated with melatonin. This study confirms, in a considerable number of patients and for a long follow-up period, the possibility to improve the efficacy of chemotherapy in terms of both survival and quality of life by a concomitant administration of melatonin. This suggests a new biochemotherapeutic strategy in the treatment of human neoplasms.

Recent advances in immunobiological knowledge have suggested the possibility of enhancing the therapeutic activity of various chemotherapeutic agents by a concomitant administration of anti-oxidant drugs and/or immunomodulating neurohormones. In particular, the pineal neurohormone melatonin (MLT), which is able to exert both antioxidant and immunomodulating effects, has been proven to enhance the efficacy of various chemotherapeutic drugs, namely cisplatin, anthracyclines and 5-fluorouracil, whereas at present there are no data about its possible influence on cytotoxic drugs effective in the treatment of colon cancer other than 5-fluorouracil, such as irinotecan (CPT-11). The present study was performed to evaluate the influence of a concomitant administration of MLT on CPT-11 therapeutic activity in metastatic colorectal cancer. The study included 30 metastatic colorectal cancer patients progressing after at least one previous chemotherapeutic line containing 5-fluorouracil, who were randomized to be treated with CPT-11 alone or CPT-11 plus MLT. According to a weekly low-dose schedule, CPT-11 was given i.v. at 125 mg/m2/week for 9 consecutive weeks. MLT was administered orally at 20 mg/day during the dark period of the day. No complete response was observed. A partial response (PR) was achieved in 2 out of 16 patients treated with CPT-11 alone and in 5 out of 14 patients concomitantly treated with MLT. Moreover, a stable disease (SD) was obtained in 5 out of 16 patients treated with CPT-11 alone and in 7 out of 14 patients treated with CPT-11 plus MLT. Therefore, the percent of disease-control achieved in patients concomitantly treated with MLT was significantly higher than that observed in those treated with chemotherapy alone (12 out of 14 vs 7 out of 16, p0.05). The only important toxicity was diarrhoea grade 3-4, which occurred in 6 out of 16 patients treated with CPT-11 alone and in 4 out of 14 patients treated with CPT-11 plus MLT, which required a 50% dose reduction. However, taken together, patients treated with CPT-11 at 50% of the planned dose showed a percent of disease control comparable to that achieved in patients who had no dose reduction (6 out of 10 vs 13 out of 20). This preliminary study shows that the efficacy of weekly low-dose CPT-11 in pretreated metastatic colorectal cancer patients may be enhanced by a concomitant daily administration of the pineal hormone MLT, according to the results previously reported for other chemotherapeutic agents. Moreover, since the dose reduction of CPT-11 does not influence its efficacy, the dose of CPT-11 for successive studies might be not greater than 70 mg/m2.

Despite the well-demonstrated stimulatory role of prolactin (PRL) on breast cancer cell growth and the possible existence of a PRL-dependency in estrogen-independent mammary tumors, the therapeutic role of the antiprolactinemic drugs in the treatment of human breast cancer has still to be investigated and defined. Previous preliminary studies have already shown that the concomitant administration of antiprolactinemic agents may enhance the efficacy of cancer chemotherapy for breast carcinoma, whereas their impact on the efficacy of the endocrine therapy is still unknown. At present, the classic endocrine therapy for breast cancer consists of anti-estrogens plus LHRH-analogue. The concomitant administration of antiprolactinemic drugs could enhance the efficacy of treatment by blocking not only the action of estrogens, but also that of another growth factor for breast cancer, such as PRL. The present phase II study was performed to evaluate the efficacy and tolerability of a polyneuroendocrine approach for breast cancer, consisting of LHRH-analogue plus the anti-estrogen tamoxifen plus a long-acting antiprolactinemic agent, cabergoline. The study included 14 consecutive metastatic breast cancer women, heavily pretreated with the standard anticancer therapies and for whom no other conventional treatment was available. The LHRH-analogue, triptorelin, was given intramuscularly at a dose of 3.75 mg every 28 days, tamoxifen was given orally at 20 mg/day and cabergoline was given orally at 0.5 mg once/week. The clinical response consisted of partial response (PR) in 4 out of 14 (29%) patients, including one who had progressed on a previous treatment with triptorelin plus tamoxifen alone. A stable disease (SD) was achieved in another 5 patients, whereas the other 5 patients had a progressive disease (PD). Mean serum levels of PRL significantly decreased on treatment within the first month of therapy, and its decline was significantly more evident in patients with PR or SD than in those with PD. The treatment was well-tolerated in all patients, and in particular no cabergoline-related toxicity occurred. This preliminary study would suggest that the association of the long-acting antiprolactinemic drug cabergoline may further enhance the efficacy of the classical endocrine therapy for advanced breast cancer with anti-estrogens plus LHRH-analogues.

Prolactin (PRL) constitutes a growth factor for breast cancer cell proliferation and abnormally elevated blood concentrations of PRL are associated with poor prognosis and reduced efficacy of antitumor therapies in metastatic breast carcinoma. It has already been demonstrated that low-dose bromocriptine, an antiprolactinemic long-acting dopaminergic drug, normalizes PRL blood concentrations in metastatic breast cancer patients with abnormally elevated PRL levels. In addition, previous clinical studies have already demonstrated a lower efficacy of chemotherapy with taxotere in metastatic breast cancer, with persistent hyperprolactinemia. We planned a controlled clinical study to evaluate the influence of a concomitant administration of the antiprolactinemic drug bromocriptine on the efficacy of chemotherapy with taxotere, in metastatic breast cancer patients progressing after chemotherapeutic combinations containing anthracyclines. The study included 30 randomized consecutive patients treated with taxotere alone or taxotere plus bromocriptine. Taxotere was given I.V. at 100 mg/m2 every 21 days for 3 cycles. Bromocriptine was given orally at 2.5 mg/day every day until the end of the chemotherapeutic treatment. Bromocriptine therapy induced a significant decline in PRL mean blood concentrations compared to patients treated by chemotherapy alone. No complete response was obtained. A partial response (PR) occurred in 5 out of 14 (36%) patients treated with taxotere plus bromocriptine and in only 2 out of 16 (13%) patients treated with taxotere alone. Moreover, a stable disease (SD) was obtained in 5 out of 16 patients treated with taxotere alone and in 7 out of 14 patients concomitantly treated with bromocriptine. Therefore, the percent of non-progressive disease (PR + SD) achieved in patients treated with taxotere plus bromocriptine was significantly higher with respect to that found in patients treated with taxotere alone (12 out of 14 vs 7 out of 16, p0.025). This preliminary clinical study would suggest that the inhibition of PRL secretion by antiprolactinemic drugs such as bromocriptine may enhance the efficacy of chemotherapy for metastatic breast cancer.

In addition to sex steroids, prolactin (PRL) may also stimulate prostate cancer growth. Abnormally high blood levels of PRL have been noted in metastatic prostate cancer patients. However, most studies have been limited to the evaluation of basal levels of PRL rather than to investigate its secretion in response to classical endocrine dynamic tests. This study was carried out to analyze PRL secretion in metastatic prostate cancer patients both at basal conditions and in response to L-Dopa and metoclopramide, which represents the most classical inhibitory and stimulatory tests for PRL secretion, respectively.The study included 12 patients with metastatic prostate cancer. On separate occasions, PRL secretion was evaluated in response to L-Dopa (500 mg orally) and to metoclopramide (10 mg i.v. as a bolus). Serum levels of PRL were measured by RIA.Mean PRL concentrations significantly increased after metoclopramide administration, even though no PRL response occurred in 6 of 12 patients. L-Dopa was unable to reduce PRL levels, which, in contrast, paradoxically significantly increased in response to L-Dopa, with mean values comparable to those achieved after metoclopramide injection.By showing a paradoxical stimulatory effect of L-Dopa on PRL secretion and a lack of response to metoclopramide in some patients, this study would suggest the existence of evident alterations in the neuroendocrine regulation of PRL release in advanced prostate cancer.

Both immunostimulatory and immunosuppressive events would occur during the immunotherapies of cancer, including interleukin 2 (IL-2) therapy. The marked increase in soluble IL-2 receptor (SIL-2R) levels during IL-2 therapy could represent a potentially negative biological effect, because of the receptor's capacity to bind IL-2 and compete for it with IL-2 cell surface receptor. Since it has been observed that macrophages stimulate in vitro the release of SIL-2R, a study was started to evaluate in vivo the role of macrophages in IL-2-induced SIL-2R rise by measuring neopterin, which is a marker of macrophage activity. The study included 9 advanced renal cancer patients, treated subcutaneously with IL-2 at 1.8 × 10 6 IU/m 2 twice daily for 5 days/week for 6 weeks. Both SIL-2R and neopterin serum mean levels significantly increased during IL-2 treatment, and the highest concentrations were reached on the second week of therapy. SIL-2R rise was significantly correlated to that of neopterin. This study, by showing a positive correlation between SIL-2R and neopterin rise, would suggest a macrophage involvement in the stimulation of SIL-2R release during IL-2 immunotherapy of cancer.

Experimental studies have shown that IL-12 plays an important role in the activation of the anticancer immune defenses. Unfortunately, at present the behavior of IL-12 secretion in human neoplasms remain to be established. In an attempt to draw some preliminary data about IL-12 secretion in human cancer, in the present study we have evaluated serum levels of IL-12 in a group of non-metastatic and metastatic solid tumor patients in relation to the survival time, and their changes in surgically treated cancer patients and in metastatic patients undergoing immunotherapy with IL-2. Mean serum levels of IL-12 were significantly higher metastatic patients (n = 40) than in those with locally limited solid neoplasm (n = 16). Moreover, within the metastatic group, the percent of 1-year survival was significantly higher in patients with abnormally elevated blood concentrations of IL-12 than in those with normal values. In the group of 10 patients surgically treated for gastrointestinal tract tumors, the surgical operation induced a significant decline in IL-12 mean serum levels. Finally, in a group of 23 metastatic renal cell cancer patients treated with IL-12 immunotherapy (6 million IU/day S.C. for 6 days/week for 4 weeks), the treatment was associated with a significant and progressive increase in IL-12 mean values. Moreover, serum mean levels of IL-12 observed in therapy in patients with response or stable disease were significantly higher than those found in progressing patients. This preliminary study seems to suggest that the evidence of high levels of IL-12 may have a favourable prognostic significance in solid tumor patients, either in baseline conditions or in response to IL-2 cancer immunotherapy.

It has been shown that low-dose subcutaneous (SC)IL-2 exerts an efficacy similar to that described for the intravenous high-doses in the immunotherapy of metastatic renal cell cancer (RCC). However, it remains to be established which could be the optimal duration of treatment. The most common schedules with subcutaneous IL-2 are generally consisting of 6 weeks of therapy, with an IL-2 dose of about 6 million IU/day. This study was performed to evaluate the efficacy of IL-2 subcutaneous immunotherapy with a duration of 4 weeks only. The study included 13 evaluable metastatic RCC patients. IL-2 has been injected subcutaneously at 6 million IU/day for 6 days/week for 4 weeks, by repeating a second cycle in nonprogressing patients after a 21-day rest period. Objective tumor regressions were achieved in 3/13 (23%) patients consisting of CR in 1 and PR in the other 2. Stable disease was obtained in other 6 patients. This preliminary study would suggest that a shorter dose-matched S.C.IL-2 immunotherapy may have a similar therapeutic efficacy in metastatic RCC. Therefore, the 4-week IL-2 S.C. immunotherapy, instead of the 6-week schedule could become the standard immunotherapeutic schedule, with following decreased cost and toxicity.

Several clinical studies have demonstrated the efficacy of subcutaneous immunotherapy with Il-2 alone in metastatic renal cell carcinoma (RCC). In an attempt to better define the clinical parameters which may predict the efficacy of treatment, the present study shows the results obtained with subcutaneous Il-2 alone in 91 evaluable metastatic RCC patients. IL-2 was injected subcutaneously at 3 million IU twice/day for 5 days/week for 6 weeks, corresponding to one immunotherapeutic cycle. In nonprogressing patients, a second cycle was given after 28-day rest period. A complete response (CR) was achieved in 2/91 patients. Moreover, 19/91 patients had a partial response (PR). Therefore, objective response (OR) rate was 21/91 (23%) patients. Stable disease (SD) was achieved in 41 patients, while the remaining 29 patients had a progressive disease (PD). OR rate was significantly higher in patients with a long disease-free survival than in patients with synchronous metastases, in nephrectomized patients than in the non-nephrectomized ones, and in patients with high than in those with low PS. The survival obtained in patients with CR or PA was significantly longer with respect to that found in patients with SD or PD. The toxicity was substantially low in all patients. This study confirms that the subcutaneous immunotherapy with IL-2 alone is an effective and well tolerated therapy of metastatic RCC.

Despite the efficacy of IL-2 in the treatment of metastatic renal cell carcinoma (RCC), the prognosis of patients with synchronous metastases still remains poor. Nephrectomy itself, as well as other surgical operations, may further suppress the antitumor immune response. Previous studies suggested that the preoperative injection of IL-2 may neutralize surgery-induced lymphocytopenia in advanced colon cancer. On this basis, a pilot randomized study was performed in an attempt to evaluate the effects of a preoperative administration of IL-2 on postoperative lymphocyte numbers and on the survival in advanced RVV patients with more than 3 synchronous metastases. The study included 20 consecutive patients, who were randomized to receive nephrectomy alone or nephrectomy plus preoperative subcutaneous immunotherapy with IL-2 (18 million IU/day for 3 days). Then, all patients underwent postoperative immunotherapy with IL-2 (6 million IU/day for 5 days/week for 6 weeks). Surgery-induced lymphocytopenia was completely abolished by IL-2 preoperative injection. The frequency of postoperative complications was significantly higher in controls than in patients preoperatively treated with IL-2. On the contrary, significant differences between control and patients preoperatively treated with IL-2 were observed neither in the clinical response to IL-2 immunotherapy, nor in the percent of 1-year survival. The results of this preliminary pilot study would suggest that IL-2 preoperative immunotherapy may neutralize surgery-induced lymphocytopenia and reduce the postoperative complications in RCC patients with synchronous metastases, without, however, influencing their prognosis in terms of survival time.

IL-12, which play a fundamental antitumor role, would be also involved in the physiological regulation of neuroendocrine and immune interactions. At present, however, there are no data about the endocrine effects of IL-12. This preliminary study was performed to investigate the acute endocrine effects of IL-12 in metastatic renal cell cancer patients. Each IL-12 injection consisted of 0.5 micrograms/kg/bw subcutaneously in the morning. The study has evaluated the effects of 6 different injection cycles. Serum samples were collected before, and 4, 8 and 12 hours from IL-12 injection. In each sample, we have measured by the RIA method serum levels of GH, PRL, TSH, FSH, LH, T3, T4, cortisol, testoterone, estradiol and the pineal hormone melatonin. No significant change occurred in TSH, FSH, LH, T3, T4, testoterone and melatonin mean serum levels in response to IL-12 administration. In contrast, cortisol, PRL and estradiol significantly increased after Il-12 injection. GH also increased in response to IL-12, without however, significant differences with respect to the baseline values. This preliminary study shows that the acute subcutaneous injection of IL-12 may influence the endocrine secretions in humans. In particular, IL-12 would stimulate the secretions of cortisol, PRL and estradiol. Therefore, this study would further confirm that IL-12 may act as biological response modifier in humans, not only on the immune system, but also on the neuroendocrine functions.

Polychemotherapy represents the only standard medical therapy of metastatic soft tissue sarcomas (STS), whereas the recent biotherapies with cytokines, such as interleukin-2 (IL-2), seem not to have a relevant therapeutic role. The pineal hormone melatonin (MLT), whose immunomodulating activity is well known, would seem to exert a direct cytostatic action on STS cell proliferation. Moreover, MLT has been proven to amplify IL-2 efficacy. On this basis, a pilot phase II study with low-dose IL-2 plus MLT has been performed in untreatable metastatic STS patients. The study included 13 evaluable metastatic STS patients with poor PS, who progressed on at least one previous polychemotherapeutic line. IL-2 was injected subcutaneously at 3 million IU/day for 6 days/week for 4 weeks and MLT was given orally at 40 mg/day in the evening. A partial response was achieved in one patient with leiomyosarcoma. Eight other patients had a stable disease (SD) whereas the remaining 4 patients progressed. A survival longer than 1 year was achieved in 6/13 patients and the percent of 1-year survival was significantly higher in patients with response or SD than in the progressed ones (6/9 vs 0/4). Mean increases in lymphocyte and eosinophil numbers were significantly higher in patients with response or SD than in the progressed ones. These preliminary results would suggest that immunotherapy with low-dose IL-2 plus MLT may have some impact at least on the survival time of untreatable metastatic STS patients with poor clinical conditions.

Recent experimental studies suggested that hematopoietic cell proliferation and differentiation are under a neuroendocrine control and that they change in relation to the 24-hour period. Moreover, it has been shown that the pineal hormone melatonin (MLT) plays a role in mediating the influence of the psychoendocrine system and of the lighting conditions on the hematopoiesis. Finally, MLT has appeared to regulate hematopoietic cell growth by influencing apoptosis-related mechanisms. In particular, preliminary studies have shown that the pineal hormone MLT may determine some benefits in blood cell disorders, mainly platelet diseases. On this basis, a pilot phase II study of MLT therapy was performed in patients suffering from persistent thrombocytopenia due to different causes. The study included 14 patients, and thrombocytopenia was due to bone metastatic involvement in 5, hypersplenism in 3, myelodysplastic syndrome in 3, DIC in 1, genetic factors in 1, and Werlhof's disease in the last case. MLT was given orally at 20 mg/day in the evening for 2 months. No MLT-related toxicity occurred. A normalization of platelet number was achieved in 8/14 (57%), and platelet mean number significantly increased on MLT therapy. This preliminary study would suggest that MLT may be effective in the treatment of thrombocytopenia due to different reasons, for which no effective standard therapy is available.

Several experimental studies have shown that melatonin has an oncostatic action, either by stimulating host antitumor immune defenses or by directly inhibiting the growth of some cancer histotypes, including melanoma. Our previous clinical studies demonstrated that melatonin may induce stabilization of the disease in untreatable metastatic solid tumor patients, and these results have been confirmed by others, at least in patients with metastatic melanoma. On the contrary, at present there are no data related to the possible efficacy of melatonin as an adjuvant endocrine therapy. This study was performed to investigate the impact of melatonin therapy on the disease-free survival (DFS) in melanoma patients surgically treated for regional node recurrence. The study included 30 node-relapsed melanoma patients, who were randomized to receive no treatment or adjuvant therapy of melatonin (20 mg/day orally in the evening) every day until disease progression. After a median follow up of 31 months, the percent of DFS was significantly higher in melatonin-treated individuals than in controls. The DFS curve was also significantly longer in melatonin group than in controls. No melatonin-related toxicity was observed. This preliminary study suggests that an adjuvant endocrine therapy with melatonin may be effective in preventing disease progression in node-relapsed melanoma patients.

It is known that advanced cancer patients may show abnormally low levels of IL-2. The immunotherapy with IL-2 can induce objective tumor regressions, but at present there are no data about the influence of a chronic exogenous IL-2 administration on endogenous secretion of IL-2. This preliminary study was performed to evaluate whether a prolonged IL-2 injection may be able to correct an eventual IL-2 endogenous deficiency in cancer patients. The study included 10 metastatic renal cancer patients, who underwent an immunotherapeutic cycle consisting of IL-2 at 6 million IU/day subcutaneously for 6 days/week for 4 weeks. Serum levels of IL-2 evaluated on venous blood samples collected before and 21 days after the end of IL-2 injection. Before the onset of treatment, abonormally low levels of IL-2 were seen in 6/10 patients. In patients with response or stable disease, mean levels of IL-2 observed 21 days after IL-2 cycle were significantly higher than those seen before therapy, whereas no difference occurred in those who progressed. This preliminary study would suggest that a prolonged subcutaneous injection of low-dose IL-2 may correct an eventual IL-2 endogenous deficiency in advanced cancer patients.

Preliminary results showed that IL-2 immunotherapy may be effective in the treatment of recurring advanced ovarian cancer. The pineal neurohormone melatonin (MLT) has been proven to amplify IL-2 efficacy by counteracting macrophage-mediated immunosuppression. On this basis, a pilot phase II study of low-dose IL-2 plus MLT was performed in advanced ovarian cancer patients progressing after at least 3 previous polychemotherapeutic lines. The study included 12 evaluable patients. IL-2 was injected subcutaneously at 3 million IU/day for 6 days/week for 4 weeks, by repealing the cycle after a al-day rest period in nonprogressing patients. MLT was given orally at 40 mg/day. No complete response was seen. A partial response was achieved in 2/12 (16%) patients. A stable disease was obtained in 5 other patients, whereas the remaining 5 patients progressed. The treatment was well tolerated. This preliminary study suggests that immunotherapy with low-dose IL-2 plus MLT may represent a well tolerated and promising therapy of advanced ovarian cancer progressing on standard medical treatments.

Despite its well documented unfavourable prognostic significance in several human diseases, including cancer, the cytokinic mechanisms responsible for an increased erythrosedimentation rate (ESR) still remain to be better analyzed and defined. The recent possibility to measure cytokine concentrations in the blood of patients has allowed us to explore the possible relation between ESR values and endogenous cytokine secretions. This preliminary study was performed to evaluate the relationship between ESR values and serum levels of IL-2 and IL-6, which represent the most important cytokines responsible for the activation and the suppression, respectively, of host anticancer immune reaction. The study included 33 consecutive solid tumor patients, 22 of whom showed distant organ metastases. Abnormally high values of ESR were present in 21 patients, including 18/22 metastatic patients and 3/11 nonmetastatic patients. Patients with elevated values of ESR showed significantly higher mean levels of IL-6 and significantly lower mean concentrations of IL-2 with respect to those found in patients with normal ESR values. These results would show that cancer-related increase in ESR values is associated with low levels of IL-2 and high levels of IL-6. Since IL-2 plays an essential role in the anticancer immunity and IL-6 may suppress the antitumor immune defenses, the evidence of low levels of IL-2 and high values of IL-6 in cancer patients with increased ESR values would explain the unfavourable prognostic significance of high ESR values in human neoplasms.

The recent advances in psychoneuroimmunology have demonstrated the existence of a psychoneuroendocrine control of the antitumor immunity. Our previous preliminary studies indicated the possibility of amplifying the biological and therapeutic efficacy of IL-2 cancer immunotherapy by immunomodulating neurohormones, mainly the pineal indole melatonin (MLT), in most advanced solid tumors, including those which generally do not respond to IL-2 alone. This study reports on the results obtained by low-dose IL-2 plus MLT in 200 patients with advanced solid neoplasms, for whom no other effective standard therapy was available. Non-small cell lung cancer, pancreatic adenocarcinoma, hepatocarcinoma, colon cancer and gastric cancer were the neoplasms most frequently detected in our patients. In addition, all patients had a life expectancy less than 6 months. IL-2 was given subcutaneously at 3 million IU/day for 6 days/week for 4 weeks; MLT was given orally at 40 mg/day. In non-progressing patients, a second cycle was given after a 21-day rest period; then, patients underwent a maintenance period consisting of one week of therapy every month until progression. A complete response (CR) was achieved in 4 patients (hepatocarcinoma 2; pancreas 1; gastric cancer 1), a partial reasponse (PR) was achieved in 36 patients (lung 12; liver 6; stomach 4; pancreas 3; colon 3; breast 2; miscellaneous 6). Tumor response rate (CR+PR) was 40/200 (20%) patients. Longer than one year survival was achieved in 79 (39%) patients. Toxicity was mild in all patients, and therapy was administered as a home therapy. The present study confirms in a great number of patients the possibility to induce objective tumor regressions in most advanced solid tumor histotypes by low-dose IL-2 plus MLT. Thus, immunotherapy with IL-2 and MLT may be considered as a new well tolerated and effective therapy of almost all advanced solid tumors, including those which do not respond to IL-2 alone or to chemotherapy.

At present, it is known that there are two main mechanisms responsible for cancer-related immunosuppression, mediated by macrophages and by TH2 lymphocytes. The relation existing between macrophage- and TH2-mediated immunosuppression still remains to be understood. The present study was performed in an attempt to establish which is the correlation existing in cancer patients between IL-10 and neopterin levels, which reflect TH2- and macrophage-mediated suppressive events, respectively. The study included 40 solid tumor patients and 60 healthy subjects as controls. Serum concentrations of neopterin and IL-10 were measured by the RIA method and by an immuno-enzymetric assay, respectively. Because of its possible production both by TH2 and macrophages, serum levels of IL-6 were also determined. Neopterin, IL-10 IL-6 mean concentrations were significantly higher in cancer patients than in controls. Mean values of both neopterin and IL-6 were significantly higher in metastatic patients than in those with locally limited disease. IL-10 mean levels were also significantly higher in patients with metastatic disease. IL-6 levels were significantly correlated with those of neopterin, whereas no correlation was found between neopterin and IL-10 values. This preliminary study would suggest that macrophage- and TH2-mediated immunosuppression may occur independently in solid tumors, and that it becomes more evident with disease progression.

A phase-II pilot clinical study was performed to evaluate the effects of low-dose subcutaneous IL-2 with the pineal hormone melatonin (MLT) in AIDS patients with CD4 counts below 200/mm3. The study included 11 patients. IL-2 was given subcutaneously at 3 million IU/ day in the evening for 6 days/week for 3 weeks. MLT was given orally at 40 mg/day in the evening every day, starting 7 days prior to IL-2. The treatment was substantially well tolerated, and in particular no cardiovascular or pulmonary complication occurred. An increase in CD4 cell number greater than 30% occurred in 4/11 (36%) patients, and CD4 cell mean values observed during the study were significantly higher with respect to those found before. In addition, the treatment induced a significant increase in mean number of lymphocytes, eosinophils, T lymphocytes, NK cells, CD25- and DR-positive lymphocytes. Finally, CD4/CD8 mean ratio significantly increased during the study. This preliminary clinical study suggests that the combined neuroimmunotherapy with low-dose subcutaneous IL-2 and MLT may improve the immune status also in AIDS patients with CD4 cell counts below 200/mm3, who generally do not respond to IL-2 alone.

Recent experiments suggest the possibility of modulating the efficacy of cancer endocrine therapy by the pineal hormone melatonin (MLT). In particular, it has been demonstrated that MLT may stimulate estrogen receptor (ER) expression and enhance tamoxifen (TMX) effects other than the antiestrogenic action. Therefore, MLT could amplify the efficacy of TMX also in patients with negative ER. On this basis, a randomized study was performed with TMX versus TMX plus MLT in ER-negative metastatic breast cancer patients, who were unable to tolerate further chemotherapy, because of age, low performance status and/or heavy chemotherapeutic pretreatment. The study included 40 ER-negative post-menopausal, metastatic breast cancer patients, who were randomized to receive TMX alone (20 mg/day orally) or TMX plus MLT (20 mg/day orally in the evening). No complete response was seen. Partial response rate was significantly higher in patients treated with TMX and MLT than in those, who received TMX alone (7/19 vs 2/21, p

Thrombocytopenia is a frequent haematologic complication of IL-2 immunotherapy of cancer. Preliminary results suggest a role of melatonin in the regulation of platelet production, so a study was started to evaluate the influence of the pineal hormone on IL-2-induced thrombocytopenia. Of 25 lung cancer patients, 10 were treated with melatonin alone, 7 received IL-2 alone and 8 patients were concomitantly treated with IL-2 and melatonin. Thrombocytopenia occurred in 3/7 patients treated with IL-2 alone, and in none of those treated with IL-2 plus melatonin; this difference was statistically significant. Platelet number increased during IL-2 plus melatonin, even though not significantly; on the contrary, platelet number decreased during IL-2 alone. Platelet number observed in patients treated with IL-2 plus melatonin was significantly higher than in those who received IL-2 alone. Finally, melatonin alone did not substantially influence platelet number. These results show that melatonin may abolish IL-2-induced thrombocytopenia. This might be due to an inhibitory effect of melatonin on macrophage-mediated platelet destruction, with a following increase in platelet number due to an enhanced IL-3 production in response to IL-2.

Despite the platelet production in response to IL-2, cancer immunotherapy with IL-2 tends to induce thrombocytopenia, which probably depends on an enhanced peripheral destruction. On the basis of our previous studies, this effect may be neutralized by a concomitant administration of the pineal hormone melatonin (MLT). This study was performed to investigate the influence of an immunotherapeutic combination with low-dose IL-2 and MLT on platelet number in advanced cancer patients showing persistent thrombocytopenia. The study included 14 advanced solid tumor patients, affected by thrombocytopenia due to different causes (portal hypertension: 9; previous chemotherapies: 3; DIC: 2). IL-2 was injected at 3 million IU/day subcutaneously for 6 days/week for 4 weeks, in association with MLT (40 mg/day orally). A normalization of platelet number occurred in 10/14 (71%) patients, and platelet mean number significantly increased on treatment. No important therapy-related toxicity was observed. This preliminary study would suggest that the concomitant administration of MLT is able not only to neutralize IL-2-induced thrombocytopenia, but also to increase platelet number in thrombocytopenic cancer patients.

The intravenous immunotherapy with high-dose interleukin-2 (IL-2) would constitute one of the most effective treatments of metastatic renal cell carcinoma (RCC). More recently, IL-2 subcutaneous therapy has also appeared active, either alone or in association with interferon, with results comparable to those found with the intravenous route of injection, but with a lower toxicity. On this basis, we have designed a protocol of treatment with low-dose IL-2 alone given subcutaneously as a first or a second line therapy in metastatic RCC. The study included 60 consecutive patients (pts) (M/F: 39/21, median age 56 years, range 26/74). IL-2 was given at a dose of 3 millions IU twice/day for 5 days/week, for 6 weeks, corresponding to one cycle. In non progressed pts a second cycle was repeated after a 28-day rest period. Dominant metastasis sites were, as follows: soft tissues: 8; bone: 11; lung: 29; liver: 3; liver plus lung: 7; adrenal: 2. The minimum follow-up was 18 months and the median follow-up was 34 months (range 18-48). A complete response (CR) was achieved in 2/60 (3%) pts. A partial response (PR) was obtained in 15/60 (25%). Therefore, tumor objective rate (CR + PR) was 17/60 (28%). The median duration of response was 13 months (4-33).(ABSTRACT TRUNCATED AT 250 WORDS)

the antitumor activity of IL-2 is mediated by an increase in lymphocyte number. Moreover, our previous studies have shown that therapy for 1 week/month with low-dose subcutaneous IL-2 is sufficient to maintain high levels of lymphocytes in cancer patients who have had tumor regression or stable disease (SD) in response to IL-2 immunotherapeutic cycles. This study was performed to establish whether tumor progression in cancer patients chronically treated with IL-2 may be associated with lymphocyte number decline.the study included 60 metastatic renal cell patients, who were treated with 2 induction cycles of IL-2 subcutaneous immunotherapy (6 million IU/day for 5 days/week for 6 weeks, corresponding to one cycle). Tumor regression occurred in 17/60 patients, 23 patients a SD, and the remaining 20 cases progressed. Non-progressed patients (n = 40) underwent a maintenance therapy consisting of one week of therapy every month. After a median follow-up of 18 months, 29/40 patients with response or SD had progressed. The immune investigation consisted of lymphocyte, T lymphocytes, NK cell number determination and sCD25 level detection.the mean number of lymphocytes, T lymphocytes and NK cells observed on IL-2 maintenance therapy was significantly higher than that seen before beginning the immunotherapy. Moreover, mean number of lymphocytes and mean levels of sCD25 observed at the time of tumor progression were respectively lower and higher than those seen on maintenance therapy in the same patients, without, however, significant differences.despite the importance of lymphocytes in mediating the antitumor activity of IL-2, this study shows that tumor progression in cancer patients chronically treated with low-dose IL-2 after response or SD during IL-2 induction cycles is not associated with a significant decline in lymphocyte, T lymphocyte or NK cell numbers. Further studies, carried out to analyze the functional status of immune cells at the time of tumor progression, will be necessary to define the role of immunity in cancer patients progressing under IL-2 chronic therapy.

IL-6 levels have been proven to correlate with resistance to IL-2 immunotherapy. Since IL-6 may be produced by both macrophages and TH2 lymphocytes, it is not possible to establish whether the negative prognostic significance of IL-6 levels may primarily depend on an enhanced macrophage or TH2 activation. Macrophage activation may be documented by the increase in its specific marker neopterin. In an attempt to establish whether the negative significance of IL-6 high levels prior to IL-2 immunotherapy may reflect an enhanced macrophage activation, we have investigated the relation existing between pretreatment concentrations of neopterin and response to IL-2 immunotherapy in cancer patients. The study included 20 metastatic renal cell cancer patients, who were treated with IL-2 subcutaneously at 6 million IU/day for 5 days/week for 6 weeks. Before the onset of IL-2 therapy, abnormally high serum levels of neopterin were seen in 11/20 patients. Moreover, neopterin concentrations were significantly correlated with those of IL-6. Tumor regression rate was significantly higher in patients with normal than in those with elevated levels of neopterin prior to therapy (5/9 vs 1/11, P0.05), as well as the percent of the survival at 1 year (9/9 vs 4/11, P0.01). This preliminary study would suggest that pretreatment values of the macrophage marker neopterin correlate with resistance to IL-2 cancer immunotherapy.

The advanced carcinoma of pancreas still remains an untreatable disease. Both chemotherapy and hormono-therapy seem not to prolong the survival time. Also immunotherapy with IL-2 has been shown to have no efficacy. Our experimental studies suggested the possibility of enhancing the antitumor activity of IL-2 by the administration of immunomodulating neurohormones, such as melatonin (MLT). This study was carried out to evaluate the efficacy of IL-2 plus MLT in advanced cancer of the pancreas. Fifty patients, with advanced adenocarcinoma of the pancreas, were randomized to receive chemotherapy consisting of 5-FU plus folates, endocrine therapy with LHRH and somatostatin analogues, supportive care alone or immunotherapy with subcutaneous low-dose IL-2 plus MLT. A partial response was obtained in 1/13 patients treated with chemotherapy and in 2/12 patients receiving immunotherapy; no tumor regression was seen in the other groups. The percent of survival at 1 year achieved in patients treated with immunotherapy was significantly higher than in the other groups tested (3/12 vs 1/38; p

Recent studies have shown the existence of reciprocal links between cytokine activity and immunomodulating neurohormones or neuropeptides. In particular, the pineal hormone melatonin (MLT) appears to influence IL-2 activity in cancer. The present study was performed to evaluate which interaction exists between MLT and another important cytokine, tumor necrosis factor-alpha (TNF), which is responsible for both antitumor cytolytic activity and cancer-related cachexia. In a first study, we analyzed MLT circadian rhythm under TNF administration (0.75 mg/day i.v. for 5 days) in 10 metastatic solid tumor patients. In a second study, we evaluated TNF serum levels in 10 metastatic solid tumor patients under therapy with MLT alone (20 mg/day orally in the evening for at least 1 month). In a third study, we have measured concomitantly daily serum levels of MLT and TNF in 30 patients with metastatic solid neoplasms. Nocturnal mean serum concentrations significantly increased in response to TNF injection. MLT therapy induced a significant decline in TNF mean values. Finally, patients with abnormally high MLT diurnal levels showed significantly lower TNF mean concentrations with respect to those with normal levels of the pineal hormone. This study, by showing the stimulatory effect of TNF on MLT secretion and the inhibitory action of MLT on TNF release, would suggest the existence of feed-back mechanisms operating between the pineal gland and TNF released from macrophages in human neoplasms.

Previous experimental studies have suggested the possibility to modulate the biological activity and toxicity of cytokines by immunomodulating neurohormones. In particular, the pineal hormone melatonin (MLT) has been proven to amplify the immune effects of IL-2 and to reduce its toxicity. On this basis, we decided to investigate the effect of MLT on biological activity and toxicity of another important antitumor cytokine, TNF. The study was performed in 14 metastatic solid tumor patients, for whom no effective standard antitumor therapy was available. Informed consent was previously obtained from each patient. Patients were randomized to be treated with TNF or TNF plus MLT. Recombinant human TNF was given at a daily dose of 0.75 mg intravenously for 5 consecutive days. MLT was given orally at a daily dose of 40 mg, starting 7 days before TNF. Lymphocyte mean number observed at the end of TNF infusion was significantly higher in patients treated with TNF plus MLT than in those receiving TNF alone. On the contrary, no significant difference occurred in hemoglobin, platelet and neutrophil mean values. Asthenia and hypotension were significantly less frequent in patients treated with TNF plus MLT, whereas no difference occurred in the frequency of fever and chills. Even though limited to a small number of patients, this preliminary study would suggest the possibility to modulate TNF toxicity and biological activity by a concomitant treatment with the pineal hormone MLT.

Experimental studies have shown that IL-2 may antagonize chemotherapy-induced lymphocytopenia. On this basis, we have evaluated the influence of low-dose IL-2 on lymphocyte and NK cell numbers in cancer patients treated with the anthracycline drug, epirubicin. The study included 7 metastatic breast cancer women treated with epirubicin at a dose of 25 mg/m2 i.v. weekly. IL-2 was given subcutaneously at 3 million IU/day for 6 days/week. Venous blood samples were drawn at weekly intervals, and the results were compared to those seen in 14 patients treated with epirubicin alone. Lymphocyte mean number observed on treatment was higher in patients concomitantly treated with IL-2 than in those receiving epirubicin alone, without, however, significant differences. In addition, NK cell mean number was significantly higher in patients receiving IL-2 than in those treated with epirubicin alone. These preliminary results would suggest that IL-2 may antagonize lymphocyte and NK cell declines during cancer chemotherapy with anthacyclines. Further studies will be required to confirm these results and to establish their possible influence on chemotherapy-induced tumor regressions.

It is known that IL-2 cancer immunotherapy is associated with hypotension. The present study was performed to evaluate the influence of low-dose IL-2 subcutaneous therapy on blood pressure in cancer patients with idiopathic hypertension requiring hypotensive therapy. The study included 12 patients, who received IL-2 at 6 million IU/day for at least 4 weeks. Mean values of both systolic and diastolic pressure significantly decreased under IL-2 therapy, and the hypotensive agents were interrupted within 2 weeks in 10/12 patients. Moreover, 6 of them still showed normal blood pressure values without hypotensive therapy after a median follow-up of 6 months. This preliminary study would suggest that low-dose IL-2 subcutaneous therapy may normalize blood pressure values in cancer patients with idiopathic hypertension.

Our previous experimental studies have shown that the best approach to increase the biological anti-tumour activity of interleukin 2 (IL-2) is not co-administration of another cytokine, but the association with immunomodulating neurohormones, in an attempt to reproduce the physiological links between psychoendocrine and immune systems, which play a fundamental role in the regulation of the immune responses. In particular, the association with the pineal neurohormone melatonin (MLT) has been shown to cause tumour regressions in neoplasms that are generally non-responsive to IL-2 alone. To confirm these preliminary results, a clinical trial was performed in locally advanced or metastatic patients with solid tumours other than renal cell cancer and melanoma. The study included 80 consecutive patients, who were randomised to be treated with IL-2 alone subcutaneously (3 million IU day-1 at 8.00 p.m. 6 days a week for 4 weeks) or IL-2 plus MLT (40 mg day-1 orally at 8.00 p.m. every day starting 7 days before IL-2). A complete response was obtained in 3/41 patients treated with IL-2 plus MLT and in none of the patients receiving IL-2 alone. A partial response was achieved in 8/41 patients treated with IL-2 plus MLT and in only 1/39 patients treated with IL-2 alone. Tumour objective regression rate was significantly higher in patients treated with IL-2 and MLT than in those receiving IL-2 alone (11/41 vs 1/39, P < 0.001). The survival at 1 year was significantly higher in patients treated with IL-2 and MLT than in the IL-2 group (19/41 vs 6/39, P < 0.05). Finally, the mean increase in lymphocyte and eosinophil number was significantly higher in the IL-2 plus MLT group than in patients treated with IL-2 alone; on the contrary, the mean increase in the specific marker of macrophage activation neopterin was significantly higher in patients treated with IL-2 alone. The treatment was well tolerated in both groups of patients. This study shows that the concomitant administration of the pineal hormone MLT may increase the efficacy of low-dose IL-2 subcutaneous therapy.

High levels of the macrophage activation marker neopterin have been described in metastatic cancer patients. Since macrophages may either counteract or stimulate tumor development, it is important to establish which macrophage activity is mainly related to neopterin release. The present study was carried out to evaluate neopterin levels in metastatic solid tumor patients in respect with the antitumor macrophage cytokine TNF and with soluble IL-2 receptor (SIL-2R), whose secretion is stimulated by macrophages and it is associated with the immunosuppressive status of cancer patients. The study included 35 patients with metastatic solid neoplasms. Serum levels of neopterin, TNF and SIL-2R were measured in blood samples collected during the morning. Abnormally high concentrations of neopterin were seen in 18/35 (51%) patients. Patients with high levels of neopterin showed significantly higher concentrations of SIL-2R than those with normal neopterin values, whereas no difference was found in TNF levels. This study would suggest that the increased secretion of neopterin may reflect macrophage-mediated immunosuppression in metastatic solid neoplasms, rather than to be associated with the antitumor activity of macrophages.

SIL-2R levels mainly depend on a T lymphocyte production. The mechanisms responsible for the elevated blood concentrations of SIL-2R in advanced solid tumors are still unknown. To investigate the role played by the monocyte-macrophage system on SIL-2R release, we have evaluated serum levels of SIL-2R in 10 head and neck cancer patients during GM-CSF subcutaneous administration (3 mcg/kg/day for 11 consecutive days). Serum levels of TNF and neopterin, both produced by macrophages, were also measured. SIL-2R mean concentration significantly enhanced in response to GM-CSF, and their rise positively correlated to that in TNF and neopterin values, while lymphocyte mean number did not increase during the study. The present results represent the first in vivo demonstration that SIL-2R release is related to macrophage activation, rather than to depend only on lymphocyte proliferation.

The intravenous injection of interleukin-2 (IL-2) has appeared to induce tumor regression in metastatic renal cell carcinoma (RCC). IL-2 given subcutaneously has also appeared to be effective when it is administered in association with interferon-alpha (INF), but with a lower toxicity in comparison to the intravenous route of administration. The present study was carried out to evaluate the efficacy of a subcutaneous immunotherapy with IL-2 alone in metastatic RCC. The study included 30 consecutive patients affected by metastatic RCC, 14 of whom had been pretreated with INF plus vinblastine, while the other 16 patients received IL-2 as a first line therapy of their metastatic disease. IL-2 was given subcutaneously at a dose of 3 million IU twice/day for 5 days/week for 6 consecutive weeks, corresponding to one cycle of immunotherapy. No complete response was obtained. A partial response (PR) was achieved in 10/30 (33%) patients (median duration: 7 months, range 5-25), without any significant difference between patients pretreated with IFN and nonpretreated patients (4/14 vs 6/16). Response rate was significantly higher in nephrectomized patients than in those who did not undergo nephrectomy (10/25 vs 0/5; P0.01). Moreover, response rate was significantly higher in patients with performance status (PS) greater than 40% than in those with PS lower than 40% (10/23 vs 0/7; P0.01). A stable disease (SD) was obtained in 12/30 (40%) patients (median duration 5 months, range 3-13), while the remaining 8/30 (27%) progressed. The increase in lymphocyte and eosinophil mean number was significantly higher in patients with PR or SD than in the progressed ones.(ABSTRACT TRUNCATED AT 250 WORDS)

TNF, in addition to its antitumor activity, would play an important role in the pathogenesis of cancer-related severe complications, including ARDS and DIC. Therefore, the modulation of TNF secretion could be important in the supportive care of advanced cancer patients. At present, PTX is the only drug which has been proven to be able to inhibit in vitro the release of TNF. The present study was performed to evaluate the effect of PTX on TNF blood concentrations in disseminated cancer patients with abnormally high TNF values. The study included 14 cancer patients, with initial or conclamate signs of ARDS (n = 8) or DIC (n = 6). PTX was given intravenously at a dose of 300 mg/day for 7 days. Mean serum levels of TNF significantly decreased in response to PTX therapy, and they returned to normal range in 5/14 patients. These preliminary data would suggest that PTX may be considered as a biological response modifier, capable of inhibiting TNF secretion in humans, with a following potential use in the treatment of cancer-related severe complications.

The concomitant activation of macrophage-mediated immunosuppressive events might represent one of the most important biologic factors responsible for the decreased efficacy of cancer immunotherapies, including that of interleukin (IL)-2. In previous studies, the authors observed that the increase in the soluble IL-2 receptor (SIL-2R) and neopterin levels was related to the generation of macrophage-mediated immunosuppression and associated with a reduced clinical efficacy during IL-2 cancer immunotherapy. Because both cytokines and neurohormones may influence the macrophage system, the current study was done to evaluate the effects of IL-3 and of the pineal hormone melatonin (MLT) on monocyte response to IL-2 administration.Peripheral blood monocytes were incubated with different concentrations of IL-2, IL-3, and MLT, either alone or in association.SIL-2R, neopterin, and tumor necrosis factor-alpha mean concentrations in the medium significantly increased during incubation with IL-2 at a concentration of 100 Cetus units/ml. IL-3 alone, at a dose of 10 ng/ml, also stimulated tumor necrosis factor release; no effect was found on SIL-2R and neopterin. The IL-2-induced neopterin rise was blocked by a concomitant incubation with IL-3 at a dose of 10 ng/ml. Finally, the concomitant incubation with IL-3 and MLT further inhibited neopterin release and significantly decreased IL-2-induced SIL-2R secretion.These results suggest that IL-3 alone or in association with MLT may modulate macrophage functions during cancer immunotherapy with IL-2 and decrease the IL-2-induced macrophage activation.

It is known that the anemias of chronic diseases, which often occur in neoplastic and in systemic inflammatory disorders, are characterized by high levels of ferritin associated with generally low iron concentrations, by suggesting an iron transfer defect due to unknown factors. Since both chronic inflammatory diseases and advanced neoplasms are characterized by alterations in the endogenous production of cytokines, a possible involvement of interleukins in chronic disease-related anomalies of iron metabolism cannot at present be excluded. The present study was carried out to investigate the effect of low-dose IL-2 subcutaneous immunotherapy (3 million IU/day for 6 days/week for 4 weeks) on ferritin, transferring and iron serum levels in cancer patients. Six patients with metastatic gastrointestinal carcinomas were evaluated. Ferritin mean levels significantly decreased during IL-2 treatment, and this finding was associated with a significant increase in transferrin values. Iron mean levels increased in response to IL-2, without, however, significant differences in respect to the pretreatment concentrations. These preliminary data, by showing changes in ferritin, transferrin and iron in cancer patients during the immunotherapy with IL-2, would suggest the existence of a cytokine regulation of iron transfer from tissues to blood, perhaps by modulating the macrophage function.

A phase 2 study to evaluate the effects of a short preoperative course of interleukin-2 (IL-2) on the postoperative course of patients with cancer.Open study.San Gerardo Hospital, Monza, Italy.16 Consecutive patients with locally advanced colorectal cancer, with or without metastases.IL-2 in a dose of 9 x 10(6) IU/m2 twice daily for three days; patients were operated on within 36 hours of the cessation of IL-2 treatment.Morbidity, mortality, and changes in numbers of lymphocytes, T lymphocytes, natural killer (NK) cells, and CD25 (cluster of determination) positive cells.There was no morbidity or mortality--in particular, there were no infections even in the patients who were at highest risk. The mean numbers of lymphocytes, T lymphocytes, NK cells, and CD25 positive cells increased significantly during the postoperative period. All patients showed evidence of infiltration of lymphocytes or eosinophils (or both) into the tumour tissue.The results suggest that a three day course of IL-2 preoperatively is well tolerated, stimulates would repair, neutralizes the lymphocytopenia induced by major operation, and induces immune cells to infiltrate the tumour. Randomised studies are needed to confirm these results.

Eosinophilia, which occurs during IL-2 immunotherapy, has appeared to be due to an enhanced secretion of IL-5 and to be associated with a clinical response. Since our previous experimental studies showed that the pineal hormone MLT potentiates IL-2 efficacy, a study was started to evaluate the influence of a concomitant MLT administration on IL-2-induced eosinophilia. The study included 30 advanced solid tumor patients, 16 of whom received IL-2 alone (6 million IU/day) and the other 14 IL-2 plus MLT (10 mg/day orally at 8.00 P.M.). Eosinophil mean number was significantly enhanced during both treatments, but its increase in patients receiving IL-2 plus MLT was significantly higher than that seen in patients treated with IL-2 alone. These results show that MLT may enhance IL-2-induced eosinophilia, by suggesting that T helper lymphocyte- type 2, which is the source of IL-5, may be the target cell for MLT action.

The advanced tumours of the digestive tract are generally less responsive to conventional chemotherapies. Moreover, preliminary results with IL-2 immunotherapy also seem to show a low efficacy. On the basis of our previous studies suggesting s synergistic action between IL-2 and some neurohormones, such as the pineal indole MLT, a clinical trial was performed to investigate the clinical efficacy and tolerability of an immunotherapy with IL-2 plus MLT in patients with advanced neoplasms of the digestive tract. The study included 35 patients (colorectal cancer: 14; gastric cancer: 8; hepatocarcinoma: 6; pancreas adenocarcinoma: 7). Distant organ metastases were present in 31/35 patients. MLT was given orally at a daily dose of 50 mg at 8.00 p.m., starting 7 days before IL-2, which was given subcutaneously at a dose of 3 million IU/day at 8.00 p.m. for 6 days/week for 4 weeks, corresponding to one cycle of immunotherapy. In nonprogressed patients, a second cycle was given after a 21-day rest period. A complete response was achieved in two patients (gastric cancer: 1; hepatocarcinoma: 1). Six other patients obtained a partial response: (gastric cancer: 2; hepatocarcinoma: 2; colon cancer: 1; pancreas cancer: 1). Therefore, the overall response rate was 8/35 (23%). Stable disease was obtained in 11/35 (31%) patients, whereas the remaining 16 patients (46%) progressed. The response rate was significantly higher in untreated patients than in those previously treated with chemotherapy. Toxicity was low in all patients, who received the treatment as a home therapy. This study shows that the immunotherapy with low-dose IL-2 plus the pineal hormone MLT is a new well tolerated and effective therapy of advanced tumours of the digestive tract, mainly in gastric cancer and hepatocarcinoma.