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EST 5275 is a phase II and III study of fluorouracil plus streptozocin (5-FU plus STZ) or doxorubicin in patients with measurable progressive carcinoid tumor. Among one hundred seventy-two cases with no prior chemotherapy and no heart disease, the response rate was 22% for 5-FU plus STZ and 21% for doxorubicin, while the median response duration and median survival were 31 weeks and 64 weeks for the combination and 26 weeks and 48 weeks for doxorubicin. Thirty-three patients who failed 5-FU plus STZ crossed over to doxorubicin and achieved an 18% response. Of the thirty-five patients who failed on doxorubicin, 29% responded to 5-FU plus STZ. Hematologic toxicity was similar for both treatments; however, the 5-FU plus STZ patients experienced more vomiting but acceptable renal toxicity. Both chemotherapy regimens have antitumor activity in carcinoid tumors.

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There are five generally accepted carcinoid histologic growth patterns, i.e., insular, trabecular, glandular, undifferentiated, and mixed. To determine their possible prognostic significance, a panel of pathologists studied the growth patterns of 138 carcinoids collected from an Eastern Cooperative Oncology Group carcinoid advanced stage disease chemotherapy investigation. Survival times were measured from date of initial pathologic diagnosis of carcinoid disease to date of either death or last follow-up. Significant differences were observed in survival times between the five major growth patterns (P less than 0.001). Within the mixed growth pattern group, significant differences in survival time were also observed (P approximately 0.05). In decreasing order of median survival time in years, the growth patterns ranked as follows: mixed insular plus glandular, 4.4; insular, 2.9; trabecular, 2.5; mixed insular plus trabecular, 2.3; three pooled low incidence rate mixed growth patterns, 1.4; glandular, 0.9; and undifferentiated, 0.5. Histologic growth patterns are recommended as a stratification factor in future studies of this disease.

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Seventy-three women with metastatic breast cancer were treated with aminoglutethimide and dexamethasone. No complete responses occurred. Ten patients (16%) achieved partial responses (mean duration, 12 months). The proportions of patients responding by disease site were breast (50%), nodes (33%), skin (23%), bone (16%), lung (11%), and liver (7%). Response did not correlate with age, menopausal status, performance status, or cortisol suppression. Ninety percent of responders had had previous responses to hormonal manipulations. No responses occurred in estrogen receptor negative patients. An additional 20% of patients had disease stabilization of eight or more months (mean, 17 months). Severe bone pain was present in 47 patients and was relieved in 19. Side effects occurred in 75% but caused discontinuation of therapy in only four patients. Somnolence, nausea, rash, Cushings syndrome, and leukopenia were the most frequent side effects. Aminoglutethimide with dexamethasone is an effective hormonal treatment for metastatic breast cancer.

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Changes are reported in [14C]-formate incorporation into nucleic acids and protein of Ehrlich ascites tumor cells during exposure to methotrexate (MTX) and fluoropyrimidines. The rate of [14C]-formate incorporation into RNA, DNA, and protein in the presence of only MTX was inhibited by 82%, 91%, and 75% respectively, when compared with control rates. However, in the presence of 5-fluorodeoxyuridine (FdUrd) plus MTX, formate incorporation into RNA, DNA, and protein was inhibited by 67%, 85%, and 66%. Incubation of cells in vitro with [3H]-dihydrofolate (DHF) results in its rapid conversion to [3H]-tetrahydrofolate (THF). The THF/DHF ratio from the soluble fraction of cells that were incubated with [3H]-DHF was 43% greater in the presence of FdUrd and MTX than in the presence of MTX alone. As the rate of [3H]-dUrd incorporation into DNA was reduced by 88% and 99% by pretreating cells with 0.1 muM and 1 muM FdUrd, respectively, the inhibitory effect of MTX on [14C]-formate incorporation into (a) RNA was decreased by 63% and 46%; (b) DNA was decreased by 74% and 61%; and (c) protein was decreased by 63% and 32%. These data suggest that fluoropyrimidines can antagonize the effects of MTX on purines or nucleic acid synthesis and protein synthesis by preventing the consumption of THF for dTMP synthesis.

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Peripheral blood and thoracic duct lymph from normal dogs and dogs with a leukemic malignant lymphoma were compared for total and differential leukocyte count and lymph flow rate. Except for higher numbers of circulating atypical lymphocytes, the blood leukocyte count as well as the lymph cell count and flow rate were similar in both groups. Lymph cell differential pattersn in lymphoma dogs had higher numbers of lymphoblasts and minor cell types, plasmacytes, monocytes, and reticulum cells, plus degenerating and mitotic cells. There was a five-fold increase in the lymph leukocyte count shortly after irradiation in two lymphomatous dosg. Stained preparations of this lymph showed signs of 100% cell mortality. It was concluded that the thoracic duct lymph is a practical source of normal and cancerous lymphoid cells, and that the lymph and cells collected from dogs with malignant lymphoma are excellent models for certain studies of spontaneous neoplasia.

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We examined several characteristics of reduced forms of folate antagonists. Dihydro and tetrahydro derivatives of aminopterin and methotrexate (MTX) were chemically prepared. When titrated with dihydrofolate reductase, reduced derivatives were equipotent with the parent compounds and titrated stoichiometrically with the enzyme at pH 6 and nonstoichiometrically at higher pH conditions (pH 7.4 and above). When incubated with L1210 cells in vitro, rates of uptake of tritiated reduced compounds were significantly less in L1210 and L1210/MTX cells compared with the respective oxidized parent compounds and significantly less in L1210/MTX than in L1210 cells. Although dihydroaminopterin and tetrahydromethotrexate increased the survival rate of mice bearing L1210 tumors, these compounds had no such effect on the life-spans of animals with L1210/MTX tumors.

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Uptake and conversion of [3H]folic acid to polyglutamate derivatives by rat liver and kidney were inhibited by methotrexate or aminopterin (15 mg/kg body weight) and DL-tetrahydromethotrexate (30 mg/kg body weight). In contrast, these antagonists did not influence the conversion of L-5-formyl-[3H]tetrahydrofolic acid or L-5-methyl[3H]tetrahydrofolic acid to polyglutamine derivatives and had little effect on the uptake of reduced folate derivatives. When [3H]methotrexate, [3H]aminopterin, and DL-[3H]tetrahydromethotrexate were administered in small amounts (15 mug/kg body wieght), no metabolites of these compounds were observed. However, at higher doses of [3H]methotrexate (300 mug/kg body weight), more than 30% of the radioactivity remaining in the tissue 24 hr after administration could be attributed to a metabolite of methotrexate. This metabolite was tentatively identified as methotrexate diglutamate.

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[3H]Dihydroaminopterin, but not [3H]methotrexate or [3H]aminopterin, was rapidly taken up by resting cell of Pediococcus cerevisiae and inhibited the uptake of (-)-5-formyl-tetrahydrofolic acid to more than 90% at a concentration of 25 muM. On the other hand 5-formyl-tetrahydrofolic acid inhibited the uptake of dihydroaminopterin to a similar extent. Dihydroaminopterin was metabolized by Pediococcus cerevisiae, but not by Lactobacillus casei, to a compound tentatively identified as dihydroaminopterin diglutamate. Methotrexate or aminopterin at a concentration of 25 muM did not inhibit the uptake of 5-formyl-tetrahydrofolic acid in Pediococcus cervisiae, but inhibited the conversion of this compound to polyglutamate forms almost completely at a level of 2.5 mu M.

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Human malignant tumors have been shown to be highly resistant to the chemotherapeutic agents so far available. Since these have to be administered in high doses, hematotoxic effects occur frequently during such treatment. Androgens and anabolic steroids being potent stimulators of normal and of some forms of impaired erythropoiesis, studies were initiated in rats to assess the possibility of a protective role of these steroids against the toxicity of cyclophosphamide. The following results were obtained: 1. A single dose of cyclophosphamide (100 mg/kg) significantly lowered the erythrocyte, reticulocyte, hemoglobin, leucocyte and platelet counts. 2. An initial treatment with nandrolone phenylpropionate signifiantly reduced the decrease of both the erythrocyte and the hemoglobin counts. 3. An initial treatment with metenolone enanthate (Primobolan-Depot) completely prevented the reduction of erythrocytes in appropriate experimental conditions and significantly reduced the decrease of hemoglobins. 4. There was no effect of these steroids on the drop of granulocytes, lymphocytes and platelets. These observations suggest that combination of anabolic steroid therapy with cyclophosphamide therapy may be worthy of clinical trial in patients whose tumors are not subject to growth stimulation by androgenic steroids.

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