Faculty Bibliography

N-(Phosphonoacetyl)-L-aspartate (PALA) is a synthetic antimetabolite exhibiting striking oncolytic properties against a wide variety of experimental solid tumors. The clinical dose-limiting factor is mucocutaneous toxicity which is reversible and dose-related. Delineation of the single-agent activity of PALA in human cancer must still await results of recently activated trials.

Relevance of the carcinogenic effects of anticancer agents has arisen in the context of three circumstances: (a) when patients who have a favorable outlook without treatment receive chemotherapy, (b) when several alternate therapies with varying carcinogenic potential are available, and (c) when considering the introduction of a new drug into clinical investigation and/or clinical practice. Teratogenic effects require special attention when dealing with women in their reproductive years. Techniques to evaluate the mutagenic effects have opened up new areas of research and will be increasingly applied to the study of anticancer drugs.

After preclinical toxicologic study in baboons, we are conducting a phase I trial of malonatoplatinum, starting with 3 mg/kg and now reaching 1 mg/kg. Toxicity, mainly hematologic, was mild and our study was mainly limited by poor solubility. Regressions, which have been rare in the advanced-tumor patients, have been observed in three patients considered as clinically resistant to cisdichlorodiammino-platinum (DDP). Malonatoplatinum pharmacokinetics appeared similar to those of DDP as far as total platinum is concerned.

DON (6-diazo-5-oxo-L-norleucine) and azotomycin are glutamine antagonists that were tested in human malignancies in the 1950s. Azotomycin demonstrated significant activity in colorectal cancer. DON is probably the active form of azotomycin. Recent impressive results for both of these agents in human tumor xenografts (especially the CX-2 colon tumor) have stimulated renewed clinical interest in DON, the more readily available agent. DON mechanism of action, clinical pharmacology, previous clinical data, and current phase I studies are discussed.

We have conducted a phase II trial of cisplatinumdiamminodichloride (CPDD) which not only demonstrated its remarkable activity in embryonic carcinoma of the testes, but also in ovarian carcinoma, in melanoma, and in epidermoid carcinoma, especially of the head and of the uterus cervix. Its toxicity, manifested mainly in the digestive and renal tracts, confines its administration to hospitalized patients only. This compound is now indicated in combination therapy for the above-mentioned tumors.

Extensive investigation is taking place to overcome the nephrotoxic manifestations and the gastrointestinal intolerance of cisplatin. Various modes of administration are being explored for this purpose with different schedules, infusion durations, hydration programs, and diuretic regimens. Pharmacokinetic studies suggest that such manipulations may lead to considerable variations in cisplatin excretion and in peak plasma levels of the non-protein-bound species. The clinical impact of these pharmacokinetic alterations is not currently apparent. This should be clarified with additional studies of the behavior of non-protein-bound platinum and its relationship to clinical efficacy and toxicity.

Long-term sequelae of therapy of neoplastic disease have become an important topic, since many patients exposed to anticancer drugs will have prolonged survival. The advances which have been made in the treatment of pediatric malignancies, in fact, give particular relevance to a study of these complications. Moreover, clues as to the mechanism of action and molecular pharmacology of these agents may emerge from such studies. Herein we review both the specific organ dysfunction and the generalized effects which may become apparent as late consequences of chemotherapy.