Treatment of choriocarcinoma with a combination of cytotoxic drugs.

Abstract

It is known that both normal embryonic development in the rat and growth of the female genital tract are dependent upon the availability of folie acid (Nelson and Evans, 1949; Hertz and Tullner, 1949). It was therefore postulated by Hertz and his colleagues (Li et al, 1956; Hertz et al, 1958) that trophoblastic tumours originating in the foetal chorion might prove sensitive to folic-acid antagonists. These workers intro duced the administration of anti-folic-acid therapy to patients with malignant trophoblastic tumours and reported five complete remissions and 17 partial remissions in a series of 27 cases. Resistance to folic acid antagonists appeared to develop during therapy in some of their patients. By crude analogy with the antibiotics, it seemed likely that resistance to cytotoxic substances, especially those with an antimetabolite action, would develop less readily when used in combination. There is also some experimental evidence which suggests that combinations of cytotoxic drugs may be more effective than the same drugs used alone (Skipper et al., 1954). Augmented toxic effects on normal tissues would also be expected. The use of a combination of drugs administered concurrently in the treatment of two cases of pulmonary hypertension due to trophoblastic tumours was described briefly by Bagshawe and Brooks (1959). The present paper describes the results of combined cytotoxic therapy in six patients who had chorionic growths. Clearly the use of such combinations of drugs is largely empirical, and much work will be required to find the best combinations. The drugs chosen in the first stage of this study were the folic-acid antagonist methotrexate (4-amino-N10-methylpteroylglutamic acid), which Blocks the conversion of folie to folinic acid, and 6-mercapto purine. The latter drug has also been shown to exert a severe toxic effect on foetal tissues and acts as an antagonist of hypoxanthine and adenine. It was also decided that, should resistance to this combination of drugs develop, then a drug of the nitrogen-mustard group, such as chlorambucil, would be employed in place of the 6-mercaptopurine.