Methotrexate-albumin conjugate causes tumor growth delay in Dunning R3327 HI prostate cancer-bearing rats

Based on the rationale of a preferred albumin uptake by tumors, conjugates comprising of rat serum albumin (RSA) as a drug carrier and of methotrexate (MTX) as chemotherapeutic drug were prepared. For a comparative study of M TX-RSA and MTX we chose a slow growing Dunning R3327 HI prostate cancer mod el. In a radiopharmacologic study blood kinetics and the tumor and organ di stribution pattern of residualizingly labeled MTX-RSA were determined, and were found to be similar to that of residualizingly labeled RSA. The MTD wa s established for Copenhagen rats at a total four injections of 2 mg/kg MTX or MTX-RSA administered at days 0, 4, 8 and 12, Tumor volume measurements and tumor removal showed a small non-significant growth delay in the MTX tr eatment group, suggesting MTX resistance for the Dunning R3327 HI prostate carcinoma, In contrast, treatment with MTX-RSA resulted in a significant (5 0%) growth inhibition of the Dunning R3327 HI tumor, The cellular mechanism s responsible for MTX resistance in Dunning HI tumor cells is not known. Th e improved therapeutic effects seen during MTX-RSA treatment in this slow g rowing adenocarcinoma might be a result of prolonged tumor exposure time an d an altered cellular uptake by a lysosomal route. MTX-albumin conjugates h ave shown antitumor activity exceeding that of MTX in several tumor xenogra fts in nude mice, including human prostate cancer. The recently initiated c linical development of MTX-human serum albumin will be continued and cancer of the prostate will be included as a potential target tumor during furthe r clinical phase II testing. [(C) 1999 Lippincott Williams & Wilkins.].