Targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207 inhibits the growth of PC-82 human prostate cancer in nude mice.
BACKGROUND
Receptors for luteinizing hormone-releasing hormone (LH-RH) found in prostate cancers might be used for targeting of chemotherapeutic agents. Doxorubicin derivative 2-pyrrolinodoxorubicin (AN-201) can be linked to carrier analog [D-Lys6]LH-RH to form the targeted cytotoxic analog of LH-RH, AN-207.


METHODS
We evaluated the effects of AN-207 and its components on the growth of LH-RH receptor-positive human prostate cancer PC-82 xenografted into nude mice. Analog AN-207, radical AN-201, carrier [D-Lys6]LH-RH, or a mixture of [D-Lys6]LH-RH and AN-201 were injected intravenously once at doses of 200 nmol/kg. Tumor growth, body weight, total WBC counts, and serum prostate-specific antigen (PSA) were determined. Receptors for LH-RH on PC-82 tumors were evaluated, and the expression of mRNA for LH-RH receptors was assessed by RT-PCR.


RESULTS
Eight weeks after administration of cytotoxic analog AN-207, there was a 67.8% reduction in tumor volume (P < 0.01), 70.7% decrease in tumor burden (P < 0.01), and 36.5% decrease in serum PSA levels (P < 0.01) as compared with controls. Only one of 8 animals treated with AN-207 died. Cytotoxic radical AN-201 caused a 34.2% (not significant, NS) reduction in tumor volume with no change in serum PSA, and killed 3 of 8 mice due to toxicity. Carrier [D-Lys6]LH-RH and the unconjugated mixture of [D-Lys6]LH-RH and AN-201 had no effect on tumor growth. LH-RH receptors as well as the expression of their mRNA were found in PC-82 tumors.
Koppán
M
M
Endocrine, Polypeptide and Cancer Institute, Veterans Administration Medical Center, New Orleans, Louisiana 70112-1262, USA.
Nagy
A
A
Schally
A V
AV
Plonowski
A
A
Halmos
G
G
Arencibia
J M
JM
Groot
K
K
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D016503:Drug Delivery Systems; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011758:Pyrroles / Q000494:pharmacology; D011966:Receptors, LHRH / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured