John M. Venditti

Current results of the screening program at the division of cancer treatment, national cancer institute

Abstract The prospective screening program at the Division of Cancer Treatment, National Cancer Institute, has now been in operation for several years and is making steady progress in the identification of new synthetic compounds and natural products of potential interest for the clinic. Data are presented on four categories of drugs that have been tested in the new screening panel: (a) clinically established antitumor agents; (b) new drugs and drugs for which there is renewed clinical interest based on activity in the new screen and previously inadequate clinical trial; (c) drugs in the initial phases of clinical trial; (d) compounds in development. An analysis of the data is presented, taking into account a series of important questions that are being addressed prospectively to the new screen. Although the ability to provide definitive answers must await feedback from clinical testing of compounds recommended by the screen, some generalizations appear to be emerging, and these are discussed. A comparison is made of the activity of drugs in the treatment of human tumors growing in two sites, subcutaneously and under the renal capsule. The subrenal capsule model appears to be somewhat more sensitive to drugs than the subcutaneous model and may provide certain advantages for initial panel testing. Attention is drawn to the potential usefulness in a screening program of the newly developed clonogenic techniques for growing human tumors. The screening program at the Division of Cancer Treatment is viewed as a dynamic entity, subject to modification in accordance with acquired experience.

Eradication Of Leukaemic Cells (L1210) by Methotrexate and Methotrexate Plus Citrovorum Factor

Eradication Of Leukaemic Cells (L1210) by Methotrexate and Methotrexate Plus Citrovorum Factor

Current NCI Preclinical Antitumor Screening in Vivo: Results of Tumor Panel Screening, 1976–1982, and Future Directions

Publisher Summary This chapter discusses the current National Cancer Institute (NCI) preclinical antitumor screening in vivo. Preclinical models used by the NCI to select new drugs for clinical trial have changed periodically over the years. Changes in screening methodology have resulted from fundamental studies of biologic factors that affect the success of treatment, such as the relationship of tumor cell growth kinetics to drug responsiveness and from retrospective analyses of correlations between clinical and preclinical efficacy. The increased level of effort required to test a compound in a panel of tumors meant that the input of agents for evaluation would have to be limited. Of a number of alternatives considered, it was determined that the most reasonable approach would be to subject materials to a relatively sensitive and cost efficient in vivo prescreens-those showing a modest but reproducible.

The Enhanced Therapeutic Effect of cis-Platinum (II) Diamminodichloride against L1210 Leukemia when Combined with Cyclophosphamide or 1,2-bis(3,5-Dioxopiperazine-1-yl)propane or Several other Antitumor Agents

Mice with early or advanced leukemia L1210 were treated with the inorganic antitumor agent, cis -platinum(II) diamminodichloride [ cis -Pt(II)], alone or combined wi

The effect of reduced derivatives of folic acid on toxicity and antileukemic effect of methotrexate in mice

Abstract Mice inoculated with leukemia L1210 were treated with combinations of methotrexate (amethopterin) and one of the following folic acid derivatives: (a) folic acid, (b) dihydrofolic acid, (c) tetrahydrofolic acid, (d) 10-formyltetrahydrofolic acid, (e) 5-formyltetrahydrofolic acid (citrovorum factor), and (f) prefolic A (5-methyltetrahydrofolic acid). Daily treatment was started 3 days after leukemic inoculation. Treatment with methotrexate (MTX) alone, or in combination with folic acid, resulted in a considerable prolongation of lifetime. All other treatments resulted in leukemic death of the animals at the same time as the untreated controls; i.e. the antileukemic effect of methotrexate was blocked by the metabolite. Delayed administration of ctirovorum factor and prefolic A, after large doses of MTX, showed that both compounds were effective in reducing toxicity but had little or no effect on the antileukemic activity when given 12 to 24 hr after MTX. At 48 hr after administration of MTX neither compound protected against the toxicity of the drug. In view of the extreme sensitivity of dihydrofolic reductase to inhibition by MTX in vitro , it was of particular interest that dihydrofolic acid was able to bring about extensive reversal of the antileukemic effect and toxicity of this substance. A study of folic and dihydrofolic reductase activity in the livers of mice which had received combinations of MTX and folic acid derivatives showed that there was no difference in the extent of inhibition, regardless of whether the combination was toxic or nontoxic to the animals.

The effectiveness of the anthracycline analog 4'-epidoxorubicin in the treatment of experimental tumors: a review

SummaryThe current report presents the data of the Division of Cancer Treatment of the National Cancer Institute (NCI) on the antitumor activity of the anthracycline antibiotic 4′-epidoxorubicin in experimental tumor systems. Direct comparisons are made with doxorubicin in individual experiments, and the data are related to those of earlier studies in the form of a review of experimental activity, in order to assess the relative activity of 4′-epidoxorubicin and doxorubicin. The experimental test models utilized by the NCI for these studies included the leukemias P388 and L1210, B-16 melanoma, Lewis lung carcinoma, the colon tumors 26 and 38, and the mammary tumors CD8F1 and C3H16/C. The human tumors growing in xenograft in athymic mice included the models LX-1 lung tumor, CX-1 colon tumor, and MX-1 mammary tumor. Additional comparisons were made with the tumor models Gross leukemia, sarcoma 180, MSV-induced sarcoma, MS-2 tumor, and a variety of human tumors growing in athymic mice, as well as with in vivo toxicologic and in vitro cytotoxicity models. Although for 4′-epidoxorubicin there is only a minimal alteration of the configuration of the doxorubicin molecule, quantitative comparison of 4′-epidoxorubicin and doxorubicin revealed not only similarities but also differences in biological activity. Both drugs showed activity against a broad spectrum of experimental tumors, with 4′-epidoxorubicin more effective against some tumors and equally effective against others. 4′-Epidoxorubicin evidenced less toxicity than doxorubicin in both acute and chronic toxicity studies with retention of therapeutic effectiveness and showed reduced cardiotoxicity. With 4′ -epidoxorubicin there resulted a higher therapeutic index and therapeutic ratio, permitting the use of higher dosage and a greater margin of safety. The preclinical differences in therapeutic and toxicologic manifestations of 4′-epidoxorubicin, reflecting apparent alterations in pharmacologic properties and mode of action in comparison with doxorubicin, support the broad spectrum clinical trials of this already-demonstrated clinically active drug.

Studies on the toxicity and antileukemic action of 6-mercaptopurine in mice.

It has been observed that 6-mercaptopurine acts as a purine antagonist for Lactobacillus casei?V2 The free purines adenine, guanine, xanthine, and hypoxanthine blocked the inhibitory activity of 6-mercaptopurine for this organism in a competitive manner; 6-mercaptopurine has also been demonstrated to have an inhibitory effect on the growth of experimental tumors and human neoplash?-? However, as in the case of other known antineoplastic agents, the toxicity of the drug for the host is a limiting factor in its employment in the treatment of neoplasia. Although the triad of host-parasite-drug has long been recognized and treated in quantitative fashion in infection chemotherapy,8-1° there has been relatively little emphasis on the host-tumor-drug relationship in tumor chemotherapy. Emphasis has been placed, in our laboratory, on the development of qualitative experimental procedures for the study of the host-tumor-drug relationship. It was felt that such procedures could provide a more firm basis for evaluation of drug effectiveness and could provide additional means for study of the mode of action of drugs. Employing citrovorum factor, folic acid, and aminopterin, experimental procedures were employed which indicate that, in the mouse, the analysis of dose-response relationships may provide a basis for inhibition analysis.’l* In addition, a macrobiological assay procedure was developed which provides a quantitative description of the antineoplastic specificity of action of a drug in terms of its relative effect against the tumor and the This procedure permits the comparison of the relative antitumor specificity of action of different treatments with the same drug, as well as of different drugs. Employing these procedures, studies were undertaken on the interrelationships of host, tumor, and drug, employing 6-mercaptopurine in mice.

Combination Chemotherapy: Basic Considerations

The primary objective of an antitumor screening program is to select from the universe of synthetic and natural products, for development and introduction into the clinic, those with the greatest likelihood of usefulness in the treatment of clinical cancer. The experimental tumor screening systems that have been employed in the search for new antitumor agents have resulted in the discovery of drugs of considerable value in the treatment of human neoplasia, and for certain types of cancer chemotherapy have contributed to an increase in lifespan that approaches normal life expectancy [13, 27]. Included are Burkitt’s lymphoma, choriocarcinoma, acute lymphocytic leukemia, Hodgkin’s disease, lymphosarcoma, mycosis fungoides, embryonal testicular carcinoma, Wilms’ tumor, Ewing’s sarcoma, rhabdosarcoma, and retinoblastoma.

Evaluation of chemical agents against the plasma cell tumor LPC-1 in mice

Recent progress in the chemotherapy of human malignancy, and especially in the treatment of leukemias and lymphomas, has resulted from the discovery of more effective antitumor drugs, the optimization of treatment schedules, the increased effectiveness of supportive care, and the application of concomitant and sequential combination chemotherapy. It is beyond the scope of this chapter to review clinical results in support of this conclusion. However, much has been written with respect to the clinical efficacy of combination therapy and the reader is referred to the recent reviews of Brodsky et al. (1972), Evans (1972), Faust et al. (1972), Frei (1972), Gold and Baig (1972), Gonick (1972), Hall (1972), Krakoff (1972), Lacher (1972), Mastrangelo and Weiss (1972), Regelson (1972 a, b), and Shnider (1972); to the earlier papers of Burchenal (1969), DeVita et al. (1969), Freireich et al. (1968), Hart et al. (1969), Mandel and Rall (1969), and Henderson and Samaha (1969) and the references cited therein. In outlining the historical progression toward improved clinical therapy, Holland (1968) and Frei (1972) emphasized the increasingly effective interaction of clinical scientists with laboratory scientists. In the present chapter, an attempt is made to cite experimental studies that relate to current concepts of combination therapy. Experimental data1, both old and new, are presented when they exemplify principles of applied combination therapy.