COMPARATIVE DISPOSITION OF THE ANTINEOPLASTIC AGENT 9-NITIROCAMPTOTHECIN AND THE INACTIVE ISOMER 12-NITRO CAMPTOTHECIN IN CASE-BEARING NUDE-MICE - EFFECT OF ROUTE OF ADMINISTRATION ON TISSUE DISTRIBUTION

Purpose: 9-Nitrocamptothecin (9-NC) and 12-nitrocamptothecin (12-NC) a re synthetic structural analogues of camptothecin (CPT) which have bee n prepared to explore the structure/activity relationship of this grou p of compounds against a wide variety of experimental tumors. As part of our investigation of the pharmacology and the mechanism of tumor in hibition of these compounds, we examined the effect of route of admini stration on the distribution of tritium-labeled 9-NC and 12-NC, an act ive and a poor chemotherapeutic agent, respectively. Methods: Quantita tive whole-body autoradiography was used and our results were compared with previous results obtained with the parent compound CPT. Results: These studies revealed that, independent of the route of administrati on, both CPT derivatives were rapidly distributed to gall bladder, gas trointestinal tract and kidney. The excretion from these organs was in dicated by the high levels of radioactivity in urine (urinary bladder) and feces (large intestines). The studies also indicated that the dis tributions of 9-NC and 12-NC were qualitatively similar, but quantitat ively higher uptake of radioactivity was observed in animals treated w ith 12-NC than in those treated with 9-NC at 30 min following treatmen t. With the exception of the late sampling time (12 h after administra tion), the accumulation of radioactivity in the lungs (bronchioles) of animals that received an intravenous (i.v.) dose of 9-NC or 12-NC was higher than those treated with an intramuscular (i.m.) dose. However, the retention of drug-derived radioactivity in the tumors of mice tre ated with an i.m. dose of 9-NC was higher than that in the tumors of i .v.-treated animals and was also higher than that in tumors of animals treated with 12-NC, Conclusions: These results suggest that higher ac cumulation of 9-NC in tumor tissues than of 12-NC may contribute to th e more potent chemotherapeutic activity of the former agent. Our resul ts also suggest that i.m. injection is a more effective route of admin istration than i.v. administration.