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.(ABSTRACT TRUNCATED AT 250 WORDS)