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) fou nd in prostate cancers might be used for targeting of chemotherapeutic agen ts. Doxorubicin derivative 2-pyrrolinodoxorubicin (AN-201) can be linked to carrier analog [D-Lys(6)]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 growt h of LH-RH receptor-positive human prostate cancer PC-82 xenografted into n ude mice. Analog AN-207, radical AN-201, carrier [D-Lys(6)]LH-RH, or a mixt ure of [D-Lys(6)]LH-RH and AN-201 were injected intravenously once at doses of 200 nmol/kg. Tumor growth, body weight, total WBC counts, and serum pro state-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 a ssessed 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 com pared with controls. Only one of 8 animals treated with AN-207 died. Cytoto xic 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-Lys(6)]LH-RH and the unconjugated mixture of [D-Lys(6)]LH-RH an d AN201 had no effect on tumor growth. LH-RH receptors as well as the expre ssion of their mRNA were found in PC-82 tumors. CONCLUSIONS. The cytotoxic analog of LH-LR AN-207 powerfully inhibited grow th of PC-82 human prostate cancer with only minor toxicity. Targeted cytoto tic LH-LR analogs may be useful for treatment of prostate cancer.(C) 1999 W iley-Liss, Inc.