Observations on the Antitumor Effect of N-Dichloroacetyl-DL-Serine (FT-9045)

Abstract

It has been reported recently (1) that the sodium salt of N-dichloroacetyl-DL-serine (FT-9045) inhibited the growth of sarcoma-307 in mice. The tumors were well established and of considerable size (1 to 2 c.c. in volume). The observation that they were sensitive to the compound (while the host animals suffered no obvious ill effects) is of considerable interest. The low toxicity of FT-9045 in animals stands out in contrast to most other chemotherapeutic agents, which depress hematopoiesis and injure other body systems at dose levels which are often ineffective against neoplastic growth. In view of this, it was considered reasonably safe to carry out preliminary studies with FT-9045 on human beings with far-advanced malignant disease. Early in these trials, through a chance observation, it was suspected that an enhanced effect occurred when FT-9045 was used in combination with other antitumor agents. These agents were cyclophosphamide and x-irradiation. This report will include the results of such combinations on experimental animal tumors and in man. The synthesis and chemical properties of the sodium salt of N-dichloroacetyl-DL-serine (FT-9045) have been described in detail by Levi et al. (2). Figure 1 shows the structure of FT-9045 compared with the structures of the amino acid, serine, and chloramphenicol. The N-dichloroacetyl radical of chloramphenicol is essential for maximum antibiotic activity (3). Since chloramphenicol interferes with protein synthesis (4), it seemed logical that antimetabolites useful in cancer chemotherapy might result by modifying the structure of amino acids with this radical. Serine was modified in this manner and found to be active against experimental animal tumors. Pharmacological Properties FT-9045 is a white crystalline compound soluble to the extent of about 15 per cent in water at room temperature. In acute toxicity studies in mice it was previously reported (1) that the LD 50 was in excess of 4 grams per kilogram of body weight. It has now been demonstrated that the LD 50 lies somewhere between 15 and 20 grams per kilogram of body weight. Infusion of a cat with 7 grams per kilogram of body weight over a period of four and a half hours produced no change in heart rate, respiration, or blood pressure, and necropsy revealed no gross pathological changes. In rats and mice treated with 1 gram per kilogram of body weight, daily, for two weeks, there were no changes in the red blood cells, hemoglobin, white cells, or platelets. A group of rats treated daily for five days per week, at a dose of 2 grams per kilogram of body weight, showed a slight weight loss (10 per cent) at the end of a three-month period. FT-9045 in the antitumor dose used most frequently throughout this study (1 gram per kilogram of body weight) exerts a diuretic effect (Fig. 2). Groups containing 6 mice each (Connaught) were caged individually in small metabolic cages and urine volumes were collected and estimated in small graduated flasks.