Stewart R. Humphreys

Past failures and future possibilities in Ewing's sarcoma: Experimental and preliminary clinical results

The typical clinical course of Ewings sarcoma is characterized by the rapid development of generalized disease. The probability of subclinical metastases in the majority of patients at the time of diagnosis indicates the need for systemic therapy as an integral part of primary treatment. Studies are described with a laboratory model system which experimentally parallels the clinical situation by using a locally transplanted tumor which rapidly metastasizes. A combination of local irradiation and systemic chemotherapy on the experimental mice provided some long‐term survivors free of disease, whereas neither treatment alone was successful. A preliminary clinical trial on patients with Ewings sarcoma treated with a similar combined approach has resulted in two survivors free of disease at 52 and 44 months out of three patients so treated.

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.

Intracerebral Growth and Treatment of Leukemia L1210

&NA; A system is described which may be employed for screening agents which suppress the immune response. The test is based on the suppression of the homograft response to leukemia L1210 and resistant sublines in pretreated C57BL mice. The aklylating agents (Cytoxan, triethylene melamine, and Melphalan) and X‐irradiation exhibited marked activity in this system. 6‐Mercaptopurine was moderately effective and amethopterin was relatively inactive.

Modification of Treatment Schedules in the Management of Advanced Mouse Leukemia with Amethopterin

Summary Mouse leukemia (L1210) was grown successfully when introduced by intracerebral route. Brain tissue was rapidly infiltrated and the disease became systemic 2-3 days following I.C. inoculation. Deaths occurred somewhat sooner than when the disease was inoculated S.C. Administration of antifolic agents (amethopterin and 3′,5′-dichloroamethopterin) increased survival time.