Inhibition of in vivo proliferation of MDA-PCa-2b human prostate cancer by a targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207.
The efficacy of therapy with targeted cytotoxic luteinizing hormone-releasing hormone (LHRH) analog AN-207 consisting of superactive doxorubicin derivative AN-201 linked to carrier [D-Lys(6)]LH-RH was evaluated in vivo in nude mice bearing xenografts of MDA-PCa-2b prostate cancer line. AN-207 was administered intravenously (i.v.) at 200 nmol/kg on day 1 and at 150 nmol/kg on day 14. After 4 weeks of treatment with AN-207, tumor growth was inhibited as shown by a 63% (P<0.01) decrease in tumor volume and a 55% (P<0.05) reduction in tumor weight, compared with controls. None of the animals died after administration of AN-207 at the total dose of 350 nmol/kg, and at the end of the experiment the body weights of mice given AN-207 did not differ significantly from controls. A single injection of cytotoxic radical AN-201 at 200 nmol/kg resulted in 43% mortality. In the surviving mice, AN-201 caused a 50% inhibition in tumor volume and a 27% reduction in tumor weight, which were non-significant, as compared to the controls. After 4 weeks, serum prostate-specific antigen concentrations in mice treated with AN-207 were 65% lower than those in controls (P<0.05), while in animals given AN-201 the reduction in serum prostate-specific antigen was only 40% (NS). The expression of mRNA for LHRH receptors was detected by reverse transcriptase polymerase chain reaction (RT-PCR) in MDA-PCa-2b tumors. The present study indicates that chemotherapy targeted to LHRH receptors on tumors inhibits growth of MDA-PCa-2B prostate cancers representative of human carcinoma disseminated to the bone and progressing despite androgen withdrawal.
Plonowski
Artur
A
Endocrine, Polypeptide and Cancer Institute, Veterans Administration Medical Center, 1601 Perdido Street, New Orleans, LA 70146, USA.
Schally
Andrew V
AV
Nagy
Attila
A
Groot
Kate
K
Krupa
Magdalena
M
Navone
Nora M
NM
Logothetis
Christopher
C
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006801:Humans; D007986:Luteinizing Hormone / Q000031:analogs & derivatives; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D012333:RNA, Messenger; C104648:AN 207; D007987:Gonadotropin-Releasing Hormone; D004317:Doxorubicin; D007986:Luteinizing Hormone