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 MTX-RSA and MTX we chose a slow growing Dunning R3327 HI prostate cancer model. In a radiopharmacologic study blood kinetics and the tumor and organ distribution pattern of residualizingly labeled MTX-RSA were determined, and were found to be similar to that of residualizingly labeled RSA. The MTD was 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 treatment group, suggesting MTX resistance for the Dunning R3327 HI prostate carcinoma. In contrast, treatment with MTX-RSA resulted in a significant (50%) growth inhibition of the Dunning R3327 HI tumor. The cellular mechanisms responsible for MTX resistance in Dunning HI tumor cells is not known. The improved therapeutic effects seen during MTX-RSA treatment in this slow growing adenocarcinoma might be a result of prolonged tumor exposure time and an altered cellular uptake by a lysosomal route. MTX-albumin conjugates have shown antitumor activity exceeding that of MTX in several tumor xenografts in nude mice, including human prostate cancer. The recently initiated clinical development of MTX-human serum albumin will be continued and cancer of the prostate will be included as a potential target tumor during further clinical phase II testing.
Stehle
G
G
I Medical Clinic, University Clinic Mannheim, Faculty for Clinical Medicine Mannheim, University of Heidelberg, Germany. gerd.stehle@urz.uni-heidelberg.de
Wunder
A
A
Schrenk
H H
HH
Hartung
G
G
Heene
D L
DL
Sinn
H
H
D000818:Animals; D001835:Body Weight; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004337:Drug Carriers; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D051381:Rats; D012709:Serum Albumin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D004337:Drug Carriers; D012709:Serum Albumin; C040811:methotrexate-serum albumin; D008727:Methotrexate