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There have been nine cases reported in the English literature in which the finding of malignant cells on cervical/vaginal cytology led to the diagnosis of primary gastric cancer. We report on a patient with gastric carcinoma, metastatic to the cervix, in which the diagnosis was suspected by the finding of signet ring cells on a Papanicolaou smear of the cervix. Prior to treatment of this patient, concordance of signet ring carcinoma on cervical and ascitic fluid cytology and on cervical and gastric biopsies was documented; this has not been reported previously. Thirty-four additional cases of gastric carcinoma metastatic to the cervix are reviewed. This paper is presented to remind the clinician that, however rare, metastases from the gastrointestinal tract to the uterine cervix do occur.

Patients with locally advanced cervical cancer have a poor prognosis. The efficacy of radiotherapy is limited by the presence of large tumor volume and nodal disease. As cisplatin is a documented radiosensitizer and has activity in squamous cell carcinomas, a prospective study was designed to evaluate the toxicity and potential synergism of concurrent cisplatin (20 mg/m2 x 5 d every 21 days) and radiotherapy in locally advanced cervical cancer. Forty-three patients were studied, of which 14 were stage IB/IIA (bulky disease) and 29 were stage IIB/IIIB/IVA. Of the 32 evaluable patients, there were 29 complete responders. Of these 29 patients, 27 remain without evidence of disease, with a median follow-up of 12 months. There were no treatment-related deaths. Cisplatin and radiotherapy appear to be a well-tolerated and highly effective regimen for locally advanced cervical cancer.

Acquired resistance to chemotherapeutic agents is an important clinical problem. One preclinical model, termed multidrug resistance (MDR), is characterized by a complex phenotype of cross-resistance to biochemically unrelated antineoplastic agents, the presence of a high-molecular-weight membrane glycoprotein, and impaired accumulation of drug. To determine whether MDR is mediated in part by altered cyclic 3',5'-adenosine monophosphate (cAMP) levels, the effect of incubation with the adenylate cyclase agonist, forskolin, was investigated in the murine sarcoma S180 cell line and two MDR variants (A5-.8, A5-2.5). Basal cAMP levels in sensitive and MDR lines were not significantly different (range, 0.15 +/- 0.05 to 0.31 +/- 0.09 pmol/mg protein); however, 1-h incubation with forskolin, 10 microM, elevated intracellular cAMP 2-fold in the parent line and 43- and 35-fold in the variants. The adenylate cyclase agonists, prostaglandin E2 and cholera toxin, and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine had no significant effect on cAMP levels. To determine the effect of forskolin on doxorubicin-induced cell lethality, S180 and MDR lines were incubated with doxorubicin plus forskolin for 1 h and cloned in soft agar. Coincubation with forskolin partially reversed doxorubicin resistance in the MDR lines in a dose-dependent fashion. To determine whether this effect was mediated solely by elevation of intracellular cAMP, the inactive 1,9-dideoxy analogue of forskolin (DF) was used. Incubation with DF resulted in no elevation of cAMP levels in the sensitive or resistant cell lines; however, DF also partially reversed doxorubicin resistance in the MDR variants. Furthermore, coincubation of the A5-2.5 cell line with doxorubicin and 8-bromo cAMP, 1 mM, did not result in reversal of resistance to doxorubicin. To determine whether the reversal of resistance by the diterpenes was associated with alteration of doxorubicin transport, uptake and efflux of [14C]doxorubicin were measured. Coincubation with both forskolin and DF, 10 microM, enhanced [14C]doxorubicin uptake in the resistant cells, while drug efflux was significantly affected only in the cell line exhibiting intermediate resistance. Since both forskolin and its inactive analogue are effective in partially reversing resistance to doxorubicin and augmenting anthracycline uptake, a mechanism other than elevation of cAMP is most likely responsible.

Prior to 1974 gastric cancer was considered refractory to chemotherapy. Single agent 5-Fluorouracil, mitomycin, and the nitrosoureas produced modest response rates with no augmentation of survival as compared to historical controls. Combinations of these agents produced slight increases in survival. The addition of doxorubicin, which had no major impact as a single agent, to 5-Fluorouracil and mitomycin C in 1974 produced impressive response rates over 40%, although these early optimistic results were tempered in randomized multi-institutional trials. Nevertheless, median overall survivals appear to have increased with this regimen over historical controls, and the substitution of cisplatin or methyl-CCNU for mitomycin C in Phase II trials has produced equivalent results. Comparison with historical controls is problematic as it is unknown what role more aggressive surgery and supportive measures may have played in increasing survival. Encouraging results with combination therapy in advanced gastric cancer have suggested opportunities to employ combination chemotherapy as adjuvant therapy or together with radiation for locally advanced gastric cancer. The role of less cardiotoxic derivatives of doxorubicin remains to be more fully explored.

We have employed a rationally designed combination attempting to biochemically modulate the cytotoxicity of methotrexate (MTX), an inhibitor of de novo purine and pyrimidine synthesis, by dipyridamole (DP), a noncytotoxic modulator which blocks cellular transport of preformed nucleosides, in the treatment of 27 patients with advanced colorectal carcinoma. Doses and schedule determined from a previous phase I pharmacokinetic study were MTX at 2.5 mg orally twice a day for 4 days to begin concurrently with DP, at 75 mg orally four times daily for 8 days. One partial response was achieved in a patient who had progressed on a previous regimen of leucovorin and 5-fluorouracil. The major toxic effects observed were myelosuppression and stomatitis. Lack of efficacy could be interpreted to reflect incomplete modulation. Therefore, studies employing continuous iv infusion of DP concurrent with or a loading schedule of DP prior to administration of MTX may be required to provide adequate evaluation of such biochemically directed strategies.

Doxorubicin and the bisdioxopiperazine, ICRF 187, synergistically inhibit proliferation of murine sarcoma S180 cells in vitro. Cell cycle analysis was employed to help discriminate cytokinetic from lethal effects of the drug combination. Twenty-four-hour incubation with either agent produced dose-dependent partial G2M arrest. At high doses, ICRF 187 produced partial G2M arrest, inhibition of cell division, and continued DNA synthesis at a higher ploidy, resulting in a second G2M arrest of an 8n population. The addition of ICRF 187 to doxorubicin resulted in enhancement of cell cycle blockade at G2M. The combination also produced enhanced lethality as measured by reduced colony-forming efficiency of drug-treated S180 cells. Measurement of [14C]doxorubicin accumulation in, and effux from, ICRF 187 pretreated cells failed to reveal an effect of pretreatment with the bisdioxopiperazine on anthracycline disposition by S180 cells, suggesting that the enhanced cytotoxic and cytostatic effects do not result from increased intracellular concentrations of doxorubicin. The positive interaction between the two drugs may represent site-specific enhancement of the anthracycline effect by ICRF 187 at an intracellular target site.

Anthracycline antibiotics remain among the most potent anticancer drugs, but their efficacy is limited by the development of a dose-dependent irreversible cardiomyopathy and by the emergence of clones of tumor cells resistant to the effects of the drug. Modifications of the basic anthracycline structure have resulted in molecules that may share the activity of the parent compound, with amelioration of some toxicities, absence of cross-resistance, or activity against tumors insensitive to the parent drug. Epirubicin has a unique metabolic pathway, glucuronidation, that may result in more rapid plasma clearance and reduced toxicity as compared with doxorubicin. Epirubicin has demonstrated comparable activity to doxorubicin in breast cancer, with possibly reduced toxicity. Idarubicin is of interest because of its cytotoxic activity when given orally. Idarubicin has prolonged retention in the plasma and has equal cytotoxic activity to the parent compound. Idarubicin has demonstrated activity against acute leukemia and breast cancer; in the latter tumor category, some doxorubicin-resistant tumors have responded. Esorubicin is of interest because of its nearly absent cardiac toxicity. This agent has some activity against solid tumors and is currently being clinically tested. Aclacinomycin A is an anthracycline in which a trisaccharide is substituted for the aminosugar. Aclacinomycin A and the related compound marcellomycin are of interest as both cytotoxic and differentiating agents. Menogaril is an anthracycline with the aminosugar on the D ring; it does not exhibit cross-resistance with doxorubicin or cardiotoxicity. Mitoxantrone is a compound that is related to the anthracyclines but has a different mechanism of action. This agent has significant activity against acute leukemia and breast cancer and is currently being compared with doxorubicin. Amsacrine is another compound related to the anthracyclines that possesses major activity against acute leukemias. Minor modifications of the anthracycline molecule have had major impact on the biologic activity of these drugs. New anthracycline analogues with up to 100 times the potency of currently available anthracyclines are being developed for clinical testing, and these complex molecules retain a nearly unlimited potential for structural modification.

The bisdioxopiperazine (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)-propane (ICRF 187) abrogates doxorubicin cardiotoxicity in every mammalian species tested, but its effect on doxorubicin antitumor activity remains poorly understood. In order to better define the anthracycline-bisdioxopiperazine interaction, the ability of murine sarcoma S180 cells to form colonies in soft agar and their capability to proliferate in microtiter wells were assayed after exposure to drug at varying doses and schedules. Incubation of cell suspensions for 1 h with doxorubicin, 0.1 microgram/ml, with or without (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane, 80 micrograms/ml, produces additive cytotoxicity for the combination. Prolonged incubation (24 h) with the same drugs produces synergistic cytotoxic and antiproliferative effects at 1- and 2-log order reductions in dose. These studies indicate that the antineoplastic activity of the single agents doxorubicin and (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane is enhanced when the drugs are used in combination, and that this phenomenon is highly dose and schedule dependent.

Lithium enhances several in vitro indices of immune function, including thymidine uptake by mitogen-stimulated human mononuclear cells. To further characterize the mechanism of action of lithium and to determine whether it acts by abrogating suppressor cell activity or by enhancing helper cell function, we have compared the effects of lithium on the mitogenic response of normal, suppressor-depleted and suppressor-enriched mononuclear cell preparations. In normal cultures, lithium enhanced thymidine uptake in response to concanavalin A (Con A) and phytohemagglutinin (PHA). In the suppressor-depleted cultures, thymidine uptake after Con A stimulation was significantly higher than in normal cultures, and was further enhanced by lithium. In the suppressor-enriched system, response to PHA was significantly lower than in normal cultures, and addition of lithium reversed the observed suppression. These results indicate that lithium may be enhancing thymidine uptake in response to mitogen at least in part by abrogating suppressor cell activity. The observed increase in thymidine incorporation in the suppressor-depleted cultures suggests that lithium may also have a direct stimulatory effect on helper cell activity.

Squamous cell carcinoma of the tongue tends to be an indolent disease. Tumors that present as small, localized lesions of the anterior tongue have a median five-year survival greater than 70 percent whether treated by irradiation or surgery. Distant metastases occur in only 7.5 percent. This report describes a well-differentiated T1N0M0 squamous cell carcinoma of the anterior tongue that progressed from diagnosis to death of the patient in less than nine months. At autopsy, the tumor had disseminated widely, including simultaneous metastases to all layers of the heart. It is concluded that factors other than morphology and anatomic extent at presentation may modify prognosis in squamous cell carcinoma of the tongue.

The combination of Interferon and low-dose cyclophosphamide synergistically inhibits the growth of human breast cancer xenografts, explanted human non-small cell lung carcinoma, and other experimental tumors. To determine whether this combination would demonstrate clinical efficacy against refractory solid tumors, we used recombinant alpha-2b-Interferon, 10 MU/m2 subcutaneously three times per week, and cyclophosphamide, 25 mg orally twice daily, in 42 patients (25 renal cell carcinoma, 17 melanoma). Two patients were inevaluable due to premature removal from the study. The toxicity profile did not differ substantially from that of Interferon alone with malaise, fatigue, fevers, and chills predominating. Sixteen percent of patients experienced an alteration in mental status. Of 40 patients evaluable for response, there were two partial responders (one renal cell carcinoma, one melanoma) and four minor responders (all renal cell carcinoma). The responder with melanoma had previously failed therapy with dacarbazine (DTIC). Seventeen patients remained stable for a median follow-up of 6 months. We conclude that this regimen is well tolerated; however, the combination of Interferon and low-dose cyclophosphamide used in this way does not appear to be superior to the same dose and schedule of Interferon used alone.

Cisplatin is a chemotherapeutic coordination complex that has been evaluated extensively. It is particularly active against testicular cancer, but carcinomas of the ovary, bladder, cervix, and head and neck are also responsive. To increase efficacy and decrease toxicity, a number of platinum analogues have been developed and tested. One of these, carboplatin, is of particular interest. In clinical trials, it has demonstrated antitumor activity comparable to that of cisplatin, without evidence of significant renal toxicity or neurotoxicity. A second interesting platinum analogue is iproplatin. Preliminary phase I studies suggest reduced adverse renal and neurologic effects similar to those seen with carboplatin, with efficacy comparable to cisplatin. Attempts to overcome the dose-limiting toxicity of cisplatin by administering high-dose cisplatin (40 mg/m2/d for five days) in hypertonic saline or with thiosulfate protection are also reviewed. These techniques have eliminated nephrotoxicity as the dose-limiting toxicity of cisplatin. However, nonrenal toxicity, especially neurotoxicity, remains substantial. The extent to which high-dose cisplatin-based chemotherapy should be used in routine clinical practice has not been determined.

Biological therapy is currently being investigated in the treatment of a number of malignancies. The hypothesis for the use of this therapeutic modality involves an attempt to stimulate an already existent but perhaps suboptimal immune response to foreign protein, including tumor. Immunologic therapy appears to work best against small-volume disease, as indicated from animal studies. This condition is potentially achievable in advanced ovarian cancer, where surgery is capable of producing multi-log reduction in tumor mass, and thus immunotherapy may be an option in this disease. The attraction of biologic therapy in patients with ovarian cancer is the potential to treat relatively localized but often chemotherapy-resistant disease. In cervical cancer, the rationale for the use of interferon is somewhat different in that this disease may be a manifestation of a virally induced proliferative lesion. Thus, the antiviral properties of interferon are being investigated in both limited and advanced cervical cancer. Both of these hypothesis have pre-clinical data to support them. This paper presents the pre-clinical and clinical work currently available for consideration of future use.

There is a well documented relationship between small cell carcinoma of the lung and the amine precursor uptake and decarboxylation system of endocrine cells (APUD). We attempted to exploit this association by employing the unique radiopharmaceutical, 131I-MIBG, which is recognized and taken up by the APUD system to monitor disease activity in patients with small cell carcinoma of the lung. A total of eight patients with biopsy proven, metastatic small cell carcinoma of the lung were studied. 131I-MIBG was synthesized in our laboratory by reacting metaiodobenzylamine hydrochloride with cyanamide with subsequent solid phase radioiodination. A dose of 0.5 mCi radiopharmaceutical was injected and images obtained on a large field of view gamma camera with a high energy parallel hole collimator at 2, 24, and either 48 or 72 h. Images were compared with known focal areas of metastatic disease demonstrable on computed tomographic scan, chest roentgenogram or bone scan. We were unable to detect reproducible correlations between the images produced by conventional radiographic techniques and the images produced by our radiopharmaceutical. We conclude that this agent will probably not be useful for localization of metastatic small cell lung carcinoma.

Recombinant interferon (rIFN) modulates the cytotoxic effects of the fluorinated pyrimidine, 5-fluorouracil (5FU), in in vitro experimental tumor cell systems. In three clinical trials employing rIFN and 5FU in patients with advanced colorectal carcinoma conducted at the Albert Einstein College of Medicine, more than half the patients achieved an objective response. Of interest, the clinical spectrum of toxicities observed with this combination is different from those seen with either rIFN or 5FU alone. This novel constellation of toxicities includes a clinical syndrome characterized by watery diarrhea followed by life-threatening sepsis. Thus, careful observation and characterization of these toxicities are required. Patient education, with the goal of making patients recognize serious side effects, is important in the management of these patients.