LH-RH receptors in human colorectal cancers: unexpected molecular targets for experimental therapy.
Since the efficacy of chemotherapy can be enhanced by targeting to specific receptors on tumors, we investigated the expression of LH-RH receptors in 5 human colon cancer lines and the effects of cytotoxic LH-RH analogs on these tumors. Nude mice bearing HT-29, HCT-116, HCT-15, LoVo and Colo-320DM cancers were treated with cytotoxic LH-RH analogs AN-152 and AN-207 or their respective cytotoxic radicals doxorubicin (DOX) and 2-pyrrolino-DOX (AN-201). The reduction in tumor growth was evaluated, and cell proliferation characteristics as well as apoptosis were analyzed by histological methods. LH-RH receptors on the tumors were investigated by radioligand binding assays and their mRNA expression by reverse transcriptase-polymerase chain reaction (RT-PCR). All 5 colorectal cancer lines expressed high affinity binding sites for LH-RH, and mRNA for the LH-RH receptors. Both cytotoxic LH-RH analogs AN-152 and AN-207 powerfully inhibited growth of all colon cancers. AN-207 had the strongest effect on HT-29 and HCT-116 tumors, and AN-152 was the most effective on Colo-320DM cancers. Cytotoxic radicals AN-201 and DOX were less effective on these 3 tumors, but had effects similar to AN-152 and AN-207 on HCT-15 and LoVo carcinomas. The four cytotoxic compounds also differently affected apoptosis and proliferation rate of the various tumor lines. Our findings suggest that cytotoxic LH-RH analogs should be considered for the therapy of patients with advanced colorectal carcinoma.
Szepeshazi
Karoly
K
Veterans Affairs Medical Center and Tulane University School of Medicine, New Orleans, LA 70112, USA.
Schally
Andrew V
AV
Halmos
Gabor
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011966:Receptors, LHRH / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D011758:Pyrroles; D012333:RNA, Messenger; D011966:Receptors, LHRH; C098751:AN 204; C104648:AN 207; C080883:LHRH, lysine(6)-doxorubicin; D007987:Gonadotropin-Releasing Hormone; D004317:Doxorubicin