Effective treatment of advanced estrogen-independent MXT mouse mammary cancers with targeted cytotoxic LH-RH analogs.
Cytotoxic agents linked to hormonal carriers provide new approaches to tumor therapy, and LH-RH receptors expressed by breast cancers can be used for targeting chemotherapeutic compounds. In the present study, large, advanced estrogen-independent MXT mouse mammary cancers were treated with cytotoxic LH-RH analog AN-152 containing doxorubicin (DOX) or AN-207 incorporating superactive derivative 2-pyrrolino-DOX (AN-201). These cytotoxic hybrid molecules were administered once i.v., close to their maximum tolerated doses, at various time intervals after transplantation of tumors. The cytotoxic LH-RH analogs and the radicals alone, given at earlier stages of tumor development, inhibited growth of MXT cancers. Cytotoxic LH-RH conjugate AN-207 had significantly stronger effect than its respective cytotoxic radical, particularly when larger tumors were treated, causing 95%, 89%, 100% and 96% tumor growth reduction when administered on days 1, 7, 10 or 14, respectively. AN-152, AN-201, and DOX, given on day 14, were virtually ineffective. Histological characteristics of tumor cell proliferation and cell death were analyzed in large MXT cancers 1-4 days after treatment with AN-207 and AN-201. AgNOR scores were decreased and apoptotic indices increased after treatment of tumors with AN-207 or AN-201, but enhanced apoptosis and decreased AgNOR numbers persisted longer in the case of AN-207. In contrast to AN-201, AN-207 also increased the extent of necrosis in tumors. In conclusion, on the basis of its powerful inhibitory effect on the aggressive MXT mouse mammary tumor, the cytotoxic LH-RH analog AN-207 could be considered for treatment of advanced human mammary carcinomas that express LH-RH receptors.
Szepeshazi
K
K
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112-1262, USA.
Schally
A V
AV
Nagy
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000633:toxicity; D016503:Drug Delivery Systems; D004967:Estrogens / Q000502:physiology*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000633:toxicity; D006131:Growth Inhibitors / Q000494:pharmacology; D007275:Injections, Intravenous; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000633:toxicity
D000970:Antineoplastic Agents; D004967:Estrogens; D006131:Growth Inhibitors; D011758:Pyrroles; C098751:AN 204; C104648:AN 207; C080883:LHRH, lysine(6)-doxorubicin; D007987:Gonadotropin-Releasing Hormone; D004317:Doxorubicin