Preclinical antitumor activity of a soluble etoposide analog, BMY-40481-30

Summary

BMY-40481-30 is a new, water-soluble derivative and probable prodrug of etoposide characterized by the presence of a phosphate group in position 4′ of the E ring of the etoposide molecule. The compound was only weakly cytotoxic in vitro and, consequently, an investigation of its antitumor activity was conducted in several murine and human tumor (xenograft) models. Etoposide was administered ip or po whereas BMY-40481-30 was given ip, po or iv. The potency of the derivative, when administered parenterally, as defined on the basis of maximum tolerated dose (MTD), was less than the parent compound on a weight (mg/kg) basis in some experiments but comparable to etoposide in other instances. Comparison at the MTD of the two compounds showed that BMY-40481-30 administered ip was as active as etoposide against ip P388 leukemia. BMY-40481-30 given iv was more active than etoposide given ip in two of five experiments versus iv P388 leukemia, but the two compounds were comparably active in the other three studies. Of particular interest was the finding that the derivative was more active than the parent compound at many of the comparable (on a mg/kg basis) dose levels of both evaluated po versus iv P388 leukemia; MTD levels were not achieved, and hence not compared, for either compound using the po route of administration. Both etoposide and BMY-40481-30 yielded comparable maximum effects against ic P388 leukemia, ic L1210 leukemia, and sc B16 melanoma, but etoposide was more efficacious versus sc M5076 sarcoma. In addition to murine tumors, the HCT-116 human colon carcinoma was tested in a subrenal capsule model in athymic (nude) mice; both compounds demonstrated similar tumor inhibitory effects. Lastly, the human lung carcinomas, LX-1 and H2981, implanted sc into nude mice, showed either equivalent sensitivity to etoposide and BMY-40481-30, or a slightly enhanced sensitivity to the parent compound, in several experiments performed. BMY-40481-30 is a novel derivative and probable prodrug of etoposide with excellent solubility in water and antitumor activity generally comparable to that of the parent compound as demonstrated in several preclinical models.