Sidney Farber

Favorable response of metastatic osteogenic sarcoma to pulse high‐dose methotrexate with citrovorum rescue and radiation therapy

Ten patients with metastatic osteogenic sarcoma were treated with 6‐hour infusions of methotrexate in high dosage. Citrovorum factor was injected 2 hours later and repeated at 6‐hour intervals for 12 doses. Methotrexate infusions were repeated at intervals of 2 to 3 weeks. Dosage was escalated until response or toxicity occurred. Doses between 100 and 200 mg/kg of methotrexate resulted in disappearance of pulmonary metastases in two patients and partial regression in pulmonary or bone metastases in two others. Between courses, radiation therapy was administered to five patients, all of whom achieved a partial response. Two patients who relapsed after initial response to chemotherapy alone, responded to subsequent radiotherapy. Toxicity and side effects were unpredictable. Of 57 treatments 30% were followed by stomatitis, 23% by myelosuppression, and 7% by renal abnormalities.

Advances in chemotherapy of cancer in man.

Publisher Summary This chapter discusses that the consideration of the status of chemotherapy of cancer in man today is based upon the actual achievement of objective effects against several forms of disseminated cancer by the action of chemical substances. A review of the advances in cancer chemotherapy in small number of institutions, which have pioneered in this field, leaves no question concerning the value of these directions of research. The chapter explores that the panels are accelerating progress in the areas of organic chemistry, screening, pharmacology, biochemistry, and clinical investigation. Synthesis of new chemical compounds is proceeding in a number of directions, although most of the workers are making nucleic acid inhibitors and cytotoxic agents. The pharmaceutical industry and the university laboratories are furnishing thousands of chemical compounds for biological studies from their stock sources. The chapter concludes that the costly lag between discovery in the laboratory or in the clinic and application to the patient with cancer should be abolished or greatly shortened.

Biological aspects of human malignant melanoma

A study of the clinical behavior of human malignant melanoma in 164 patients has revealed a variety of endocrine and immunologic factors which appear to play a role in the initiation and dissemination of the disease. Genetic factors could not be established to have a statistically significant role in disease development, despite apparently high incidence of malignancy in the relatives of patients with this disease. Survival in patients with various anatomic primary sites is consistently related to development of all stages of disease dissemination. This suggests the role of host factors relatively early in the disease which may play a role in determining eventual survival.

Continuous infusion of methotrexate in children with acute leukemia

Two methods of prolonged infusion of methotrexate are described. Amounts of drug many times larger than commonly used are given. Remissions were induced in patients who were resistant to this drug when it was given orally (2.5 mg) or twice a week intramuscularly (30 mg per m2). Infusions of methotrexate lasting 18 hours, or multiples of this duration, were used for the induction of remission. Massive multiple platelet transfusions were required to protect such patients from bleeding. These studies indicate that a lack of response to customary doses of methotrexate may be due to increased tolerance of leukemic cells to the drug rather than to absolute resistance to it. The induction of remission with the above treatments is of considerable theoretical interest but of little practical value. The toxic manifestations associated with extended periods of infusion of methotrexate (longer than 18 hours) and the need of massive supportive transfusions discourage the routine use of such methods. The lesser toxicity of large doses of methotrexate given in short infusions (4 hours) and at intervals of longer than 3 weeks suggests that improved ways of using methotrexate for the maintenance of remissions may become available.

The question of stemlines in human acute leukemia: Comparison of cells isolated in vitro and in vivo from a patient with acute lymphoblastic leukemia☆

Abstract Mononuclear, lymphoblastoid (CCRF-SB) cells isolated in suspension culture from the peripheral blood buffy coat of a child with acute lymphoblastic leukemia have been non-tumorigenic in untreated neonatal Syrian hamsters. This observation is in contrast to the previously reported serial transplantability of H-SB2, a tumor produced in newborn hamsters by the direct implantation of buffy coat cells from the identical blood specimen. Cells of the CCRF-SB culture are, however, tumorigenic in newborn hamsters treated with anti-hamster thymus lymphocyte serum (ALS). Unlike H-SB2, the tumor (H-SB9) produced in hamsters by implantation of the CCRF-SB cells is dependent upon treatment of the host with ALS for transplantation, does not undergo spontaneous conversion to leukemia in the hamster host, and actively synthesizes human immunoglobulins. These, together with karyotypic and certain biochemical differences (described elsewhere) raise the possibility of the existence of different “stemlines” in this patient with acute lymphoblastic leukemia. However, the available evidence suggests that only the H-SB2 cell population represents a leukemic “stemline”. The CCRF-SB cell population more closely resembles previously described lymphoid cells derived from the peripheral blood of patients with infectious mononucleosis.

BIOLOGICAL STUDIES OF ACTINOMYCIN D

In the summer of 1954, after scientific discussions between Selman A. Waksman and Sidney Farber, a preparation of actinomycin D, made available through the kindness of S. Waksman,’ was subjected to preliminary trial in the Mouse Bioassay Unit of The Children’s Cancer Research Foundation. An evaluation of results soon indicated that this substance possessed activity of a high degree against many of the rodent tumors routinely utilized a t that time (TA-

Nutritional requirements of human leukemic cells: Asparagine requirements and the effect of l-asparaginase☆

Abstract Eight cultures of human lymphoblastic cells have been examined with respect to l -asparagine requirements. Although none of these cultures required exogenous l -asparagine for log-phase growth, or exhibited a metabolic response to exogenous l -asparagine, all were inhibited by l -asparaginase, both in the presence and absence of exogenous l -asparagine. Study of samples of l -asparaginase of known degrees of purity indicated that inhibition was related to specific enzyme activity, rather than to the possible presence of a non-specific “toxic factor”. The most likely explanation of these observations is that these human lymphoblastic cells have sufficient asparagine synthetase activity (which may be population-dependent) to satisfy their metabolic requirements for l -asparagine, and that l -asparaginase interferes with the utilization of this endogenous l -asparagine. It is suggested that the degree of asparagine synthetase activity exhibited by a given population of cells might be a better index of sensitivity to l -asparaginase than is the metabolic response of that population to exogenous l -asparagine.

Coagulation-Promoting and Inhibitory Properties of Modified Thrombin Preparations

Summary An alcohol precipitate obtained from heated bovine thrombin preparations promoted the early phases of the coagulation mechanism, but did not clot fibrinogen in the manner of the unheated preparation. These materials inhibited bovine thrombin at lower concentrations that human thrombin in the clotting of fibrinogen.