A prostate-specific antigen (PSA)-activated vinblastine prodrug selectively kills PSA-secreting cells in vivo.
Currently, there is no therapy for men with androgen-refractory prostate cancer that substantially extends survival. This report characterizes by in vitro and in vivo techniques a new chemotherapeutic that is composed of desacetyl-vinblastine covalently linked to a peptide that contains a peptide bond that can be hydrolyzed by prostate-specific antigen (PSA). This compound (referred to as vinblastine-conjugate) is minimally toxic to cells in culture which do not express PSA. In the presence of PSA, the peptide moiety is hydrolyzed, generating several highly toxic metabolites that contain vinblastine. Animals bearing PSA-positive human prostate tumors that were treated with the vinblastine-conjugate experienced a >99% reduction in PSA serum level. In contrast, animals bearing PSA-positive human prostate tumors treated with the cytotoxic metabolites derived from the PSA hydrolysis of the vinblastine-conjugate showed a nonsignificant change in both PSA and tumor weight values. The cell killing activity of the vinblastine-conjugate is PSA dependent because animals bearing non-PSA-producing human tumor xenografts had a nonsignificant increase in tumor weight after vinblastine-conjugate treatment. Exploratory efficacy/toxicity studies in LNCaP tumor-bearing nude mice were conducted with animals treated for 5 consecutive days with various doses of either the vinblastine-conjugate or a PSA-generated toxic metabolite (desacetyl-vinblastine). The desacetyl-vinblastine treatment resulted in 10-70% mortality with a very slight effect on tumor growth. In contrast, vinblastine-conjugate treatments resulted in no mortality, good to excellent antitumor efficacy, very slight to slight peripheral neuropathy and myelopathy, and slight to severe testicular degeneration. Similar treatment of beagle dogs with the vinblastine-conjugate showed even less toxicity. These data support the use of the PSA-hydrolyzable vinblastine-conjugate as an experimental therapy for prostate cancer in man.
DeFeo-Jones
Deborah
D
Brady
Stephen F
SF
Feng
Dong-Mei
DM
Wong
Bradly K
BK
Bolyar
Trina
T
Haskell
Kathleen
K
Kiefer
David M
DM
Leander
Karen
K
McAvoy
Elizabeth
E
Lumma
Patricia
P
Pawluczyk
Joseph M
JM
Wai
Jenny
J
Motzel
Sherri L
SL
Keenan
Kevin
K
Van Zwieten
Matthew
M
Lin
Jiunn H
JH
Garsky
Victor M
VM
Freidinger
Roger
R
Oliff
Allen
A
Jones
Raymond E
RE
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000627:therapeutic use*; D004285:Dogs; D004317:Doxorubicin / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000378:metabolism / Q000627:therapeutic use*; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D013045:Species Specificity; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000378:metabolism / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D014747:Vinblastine; D004317:Doxorubicin; D017430:Prostate-Specific Antigen