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Antitumor Activity and Preliminary Drug Disposition Studies on Chartreusin (NSC 5159)¹

Cancer Research Unit, The Upjohn Company, Kalamazoo, Michigan 49001 [J. P. M., G. L. N., S. L. C., M. I. R.] and National Cancer Institute, NIH, Silver Spring, Maryland 20910 [J. D. D.]

Chartreusin has exhibited significant therapeutic activity against three experimental mouse tumors (ascitic P388, L1210 leukemia, and B16 melanoma) when tumor cells were inoculated i.p. and drug was administered i.p. In further testing against P388 leukemia, no activity was observed when drug was administered p.o., s.c., or i.v.

Chartreusin was very slowly absorbed from the small intestine, thus explaining the lack of activity when administered p.o. When given i.p., the drug precipitated in the peritoneal cavity and was slowly absorbed over several hr. The strong activity observed by this route was related to the prolonged and intimate contact of drug with tumor cells in the peritoneal cavity. Upon s.c. administration, extensive precipitation occurred. Subsequent dissolution and absorption from the injection site were very slow, and measured plasma and tissue levels were quite low. Biliary excretion of chartreusin, the predominant route of elimination, was very rapid, with 80 to 100% of the dose appearing as unchanged drug in the bile within 6 hr after i.v. administration. Rapid biliary excretion after i.v. administration was reflected in a rapid decline in plasma and tissue concentrations to levels (shown by in vitro cell kill experiments) less than those necessary to kill P388 cells. When the bile ducts of i.v.-dosed leukemic mice were ligated, therapeutic activity was observed, confirming that the physiological disposition of chartreusin exerts a major influence on its therapeutic utility.

¹ This study was supported in part by Contract NO1-CM-43753 with the Division of Cancer Treatment, NIH, Department of Health, Education and Welfare.

² To whom requests for reprints should be addressed.

Received 11/ 5/76. Accepted 3/ 2/77.

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