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A phase I study of NKT-01 (deoxyspergualin), which is a derivative of an antitumor antibiotic, spergualin, was performed by a cooperative study group. NKT-01 was given intravenously by 3-h infusion. The effect of single administration was studied prior to evaluation of daily administration for 5 consecutive days. In all, 5 and 33 patients with various malignancies, including leukemia, were entered into the trials of single and daily administration, respectively. In the single-administration study, all patients were evaluable and no clear adverse effect was observed at doses ranging from 20 to 320 mg/m2. In the daily-administration study, 28 evaluable patients (16 men and 12 women; median age, 55.5 years) were treated with a daily dose of 20-500 mg/m2. Toxicities such as myelosuppression, mild nausea/vomiting, anorexia, alopecia, tongue and perioral numbness, and hypotension were observed dose-dependently during or after the treatment. Grade 2 leukopenia, thrombocytopenia, and anemia were experienced at a dose of 500 mg/m2. These usually recovered to normal values by approximately 3 weeks after treatment. A pharmacokinetic analysis of single administration revealed rapid plasma clearance, with mean half-lives for the alpha and beta phases being 28 min and 6.9 h, respectively. Approximately 12% of the infused dose was excreted into the urine in unmetabolized form. The pharmacokinetic parameters obtained after 5-day administration were similar to those recorded after single administration. Concerning treatment response, a transient but significant reduction in the number of leukemic cells was observed in one patient with adult T-cell leukemia. In this study, perioral numbness, hypotension, and hematological toxicity were concluded to be dose-limiting, with the maximal acceptable dose being 500 mg/m2. The recommended dose for a phase II study of NKT-01 against solid tumors was judged to be 400 mg/m2 given daily by 3-h infusion for 5 days, every 3 weeks. In hematological malignancies, however, higher myelosuppressive schedules of administration should be investigated. [ABSTRACT FROM AUTHOR]

The comparative pharmacokinetics of doxorubicin (DOX) were investigated in five hemodialysis (HD) and eight non-hemodialysis (non-HD) patients who were infused with a 40- to 60-mg dose of DOX at a constant rate over 30 min. A significant difference was observed in the total body clearance (Cl tot) of DOX between HD and non-HD patients. The area under the curve (AUC) for both DOX and doxorubicinol (DOXol), an active metabolite, showed increases of approximately 1.5 and 3 times in HD patients as compared with non-HD patients. Although these differences were not statistically significant (P < 0.1), the mean residence time (MRT) of DOX and DOXol in HD patients showed a 2-fold increase in comparison with those in non-HD patients. Compartmental analysis indicated that the greater AUC values and longer MRT of DOX and DOXol in HD patients resulted from the lesser DOXol formation and disappearance of rate constants. As a consequence of the decrease in Cl tot for DOX and the marginal hemodialysis clearance of both DOX and DOXol, the present study suggests that the exposure to DOX and DOXol obtained in HD patients greater than achieved in non-HD patients. Careful attention should therefore be paid to HD patients receiving DOX. [ABSTRACT FROM AUTHOR]

A randomized clinical trial of combination chemotherapy for adult acute lymphoblastic leukemia (ALL) with doxorubicin, vincristine and prednisolone with and without L-asparaginase (AdVP vs L-AdVP) was conducted, involving 58 institutions throughout Japan. After reaching complete remission (CR), patients were treated with the same regimen for more than 2 years. Among 166 evaluable cases of the 198 cases enrolled, CR rates were 63.1% (53/84) with AdVP and 64.6% (53/82) with L-AdVP (P = 0.837). Median survival times and 7-year survival rates were 12.7 months and 21.2% with AdVP, and 16.0 months and 22.3% with L-AdVP (P = 0.955 by generalized Wilcoxon test [GW], P = 0.952 by log-rank test [LR]). Median disease-free survival times and 7-year survival rates were 13.5 months and 23.8% with AdVP and 17.0 months and 30.6% with L-AdVP, showing some increments for L-AdVP but no statistical significance (P = 0.141 by GW, P = 0.300 by LR). Among the cases of extramurally confirmed FAB subtypes, CR rates were 75.9% (63/83) for the L1 subtype and 51.3% (39/76) for the L2 subtype (P = 0.001). As to adverse effects, pancreatitis was complicated more frequently in L-AdVP than in AdVP (P = 0.039). Other side effects such as hyperbilirubinemia, diabetes mellitus, diarrhea and hypofibrinogenemia were observed more frequently with L-AdVP, but with no statistical significance. Thus, addition of a single course of L-asparaginase in the induction phase of combination chemotherapy with doxorubicin, vincristine and prednisolone did not significantly enhance the effect of antileukemic treatment of adult ALL. [ABSTRACT FROM AUTHOR]

Liblomycin (NK313) is a bleomycin analog that has proved to be associated with less pulmonary toxicity and with more potent antitumor activity than bleomycin in animal tumors. In a phase I study, pulmonary toxicity was not observed, whereas myelosuppression was the dose-limiting factor. The maximum tolerated dose was 140 mg/m2 given once a week for 4 weeks. In the present phase II study, patients with malignant lymphomas received liblomycin at 80 or 100 mg/m2 by intravenous infusion over 15 min once a week for 4 weeks. A total of 39 patients were entered, and 31 [4 with Hodgkin's disease (HD) and 27 with non-Hodgkin's lymphoma (NHL)] were evaluable. The median age of the patients was 52 years (range, 22-74 years), and their performance status ranged from 0 to 3. In all, 28 of the patients had a history of intensive anticancer chemotherapy. Responses were evaluated according to WHO criteria. We obtained 1 complete remission and 9 partial remissions (PRs), for an overall response rate of 37%, in the 27 patients with NHL, whereas 1 PR was achieved in the 4 patients with HD. In all, 9 PRs (32.1%) were obtained in patients who had been exposed to prior chemotherapy, including 4 PRs (33.3%) in 12 patients who had previously been treated with bleomycin. Myelosuppression and nausea and vomiting were the major toxicities, which occurred in about 50% of the patients, and myelosuppression was severe in two patients treated at a dose of 100 mg/m2. We concluded that liblomycin demonstrated significant antitumor activity against malignant lymphomas. [ABSTRACT FROM AUTHOR]

We investigated the possibility of shortening the interval between courses of the commonly prescribed 28-day MVP (mitomycin C, vindesine, and cisplatin) regimen in patients with non-small-cell lung cancer (NSCLC). We conducted a nonrandomized phase II study using recombinant human granulocyte colony-stimulating factor (G-CSF, Chugai) to explore the possibility of shortening the cycle length to 21 days and compared the results with those obtained in historical controls who had received the standard 28-day regimen. A total of 40 patients, 37 of whom were evaluable, were entered in the 21-day treatment group of the trial and were compared with 38 historical controls who had received standard 28-day cycles of MVP at our institution. Patients in the 21-day group received mitomycin C at 8 mg/m2 on day 1, vindesine at 3 mg/m2 on days 1 and 8, and cisplatin at 80 mg/m2 on day 1, with the schedule being repeated every 21 days. Controls had received the same regimen, albeit at 28-day intervals. G-CSF was given s.c. to the patients in the 21-day group at a daily dose of 2 micrograms/kg from day 2 to day 21 of every MVP cycle. The administration of G-CSF to these patients accelerated neutrophil recovery as compared with that observed in the historical controls. Significant differences were found between the two groups in terms of mean neutrophil nadirs (2666/microliters in the first cycle and 1369/microliters in the second for the G-CSF group vs 416/microliters in the first cycle and 685/microliters in the second cycle for the control group; P < 0.0001) and the mean duration of neutropenia (< or = 1000/microliters; 1.0 day in the first cycle and 1.7 days in the second for the G-CSF group vs 8.0 days in the first cycle and 6.9 days in the second for the control group; P < 0.0001). This enabled 32 (86%) of 37 patients in the G-CSF group to complete > or = 2 cycles on schedule. In 10 patients, the bone marrow aspirates taken after G-CSF administration showed increases in band neutrophil and myelocyte percentages. In conclusion, MVP treatment of patients with NSCLC at 21-day intervals is possible with the support of G-CSF. [ABSTRACT FROM AUTHOR]

The effects of recombinant granulocyte colony-stimulating factor (rG-CSF) on the myelosuppression, especially neutropenia, induced by cancer chemotherapy in patients with urogenital cancer were investigated in a randomized, controlled clinical study. In this study, rG-CSF was given subcutaneously at a dose of 2 micrograms/kg per day for 14 consecutive days. Changes in neutrophil counts were compared between the first (no rG-CSF) and second cycles (rG-CSF treatment period) of chemotherapy. rG-CSF administration was found to be effective in reducing the duration of neutropenia, in elevating the neutrophil nadir, and in reducing recovery time. Based on comparisons between the randomized rG-CSF treatment group (with rG-CSF) and the control group, treatment with rG-CSF resulted in the moderation or prevention of neutropenia and the acceleration of recovery. These results demonstrate that in chemotherapy of patients with urogenital cancer, in which neutropenia is a dose- or schedule-limiting factor, the concomitant use of rG-CSF may enable an increase in the dose (higher single dose or increased dose per unit of time) or shorten the chemotherapy period. [ABSTRACT FROM AUTHOR]

UFT is a compound in which futraful (FT) and uracil are combined at a ratio of 1:4. UFT was given orally at a daily dose of 300-600 mg in a phase II study. Pooled data on a UFT phase II study of 438 evaluable patients, at 104 institutions revealed a response in carcinoma of the stomach (27.7%), pancreas (25.0%), gallbladder and bile duct (25.0%), liver (19.2%), colon and rectum (25.0%), breast (32.0%), and lung (7.0%). The mainly gastrointestinal toxicity resulted in anorexia (24.3%), nausea and vomiting (12.5%), and diarrhea (11.8%). On the other hand, hematological toxicity was rare and mild. To analyze the life-prolonging effect of the therapy, a cohort study was carried out in 438 cases collected in the UFT phase II study 5 years after the commencement of the therapy. The 50% survival time for 185 patients with gastric cancer was 185 days. The corresponding times in 54 patients with colorectal cancer and 49 with breast cancer were 227 and 505 days, respectively. A historical comparative study of UFT and FT, which was administered in the same institutions for equal evaluation, revealed that UFT had a significantly better effect than FT without more pronounced side effects with the equivalent dose schedule. In conclusion, UFT can be considered a useful against cancers over a broad spectrum, especially in gastrointestinal cancer. [ABSTRACT FROM AUTHOR]

A phase I clinical and pharmacokinetic study of recombinant human tumor necrosis factor (rH-TNF) was conducted in a single dose schedule in 33 patients with advanced cancer. rH-TNF was given by i.v. infusion over 30 min with a starting dose of 1 x 10(5) units/m2. The dose was escalated up to 16 x 10(5) units/m2 according to the modified Fibonacci scheme. Toxic effects were similar but not identical to those reported with interferons and interleukin-2, and included fever, rigors, nausea and vomiting and anorexia in a non-dose-dependent manner, and hypotension, leukocytosis, thrombocytopenia and transient elevation of transaminases (SGOT and SGPT) in an approximately dose-dependent manner. DIC syndrome was observed in one patient who had received 16 x 10(5) units/m2. The dose-limiting toxicities were hypotension, thrombocytopenia and hepatotoxicity, and the maximum tolerated dose in a single i.v. infusion of rH-TNF appeared to be 12 x 10(5) units/m2 when thrombocytopenia and elevation of SGOT and SGPT were taken as the dose-limiting toxicities. However, if hypotension was included, the maximum safely tolerated dose appeared to be 5 x 10(5) units/m2. [ABSTRACT FROM AUTHOR]

Elevations of serum lipid peroxide levels were demonstrated in mice after an equitoxic dose of doxorubicin. When BDF1 mice were injected with doxorubicin (20 mg/kg body weight, IP), lipid peroxide levels in sera were elevated 1 day after the injection and the levels declined on subsequent days. 5-Fluorouracil (400 mg/kg body weight, IP) never changed the peroxide levels in serum. Furthermore, it was found that the co-administration of [dl]-alpha-tocopheryl acetate or coenzyme Q10 IM strongly inhibited the doxorubicin-induced elevation of lipid peroxides in serum. The effectiveness of [dl]-alpha-tocopheryl acetate or coenzyme Q10 in reducing the lethality of doxorubicin in mice was also confirmed. These results indicate that the measurement of serum 2-thiobarbituric acid-reacting substances provided a useful measurement of lipid peroxide levels, which may be involved in some way with doxorubicin toxicity, and that the administration of antioxidants provide protection against some of the side effects of doxorubicin. [ABSTRACT FROM AUTHOR]