GROWTH-INHIBITION OF HUMAN OVARIAN CANCERS BY CYTOTOXIC ANALOGS OF LUTEINIZING-HORMONE-RELEASING HORMONE

Background: Receptors for luteinizing hormone-releasing hormone (LH-RH ) are found in nearly 80% of human ovarian cancers. The chemotherapeut ic agent doxorubicin can be linked to [D-lysine(6)]LH-RH to form a cyt otoxic analogue (AN-152) that may have greater specificity for tumor c ells. This study was conducted to investigate the effects of AN-152 on the growth of LH-RH receptor-positive OV-1063 human epithelial ovaria n cancers. Methods: Nude mice bearing human ovarian tumors, OV-163 or UCI-107 (LH-RH recpetor negative), were injected intraperitoneally wit h saline (control) or with equimolar doses of AN-152 or doxorubicin; e xperiments involving mice with OV-1063 tumors also included groups tha t were administered [D-lysine(6)]LH-RH either alone or in combination with doxorubicin. Tumor volume, weight, doubling time, and burden (i.e , tumor weight/body weight) as well as tumor apoptotic and mitotic ind ices were determined. The levels of receptors for LH-RH and epidermal growth factor (EGF) and their messenger RNAs were measured by use of r adioreceptor and reverse transcription-polymerase chain reaction assay s respectively. Results: The growth of OV-1063 ovarian tumors in nude mice as based on reduction in tumor volume, was inhibited significantl y (all P,.05, two-sided) 4 weeks after treatment with AN-152, even at the lowest dose tested (413 nmol/20g weight); the toxic effects of an equivalent dose of doxorubicin caused substantial mortality. High-affi nity receptors for LH-RH and EGF were found on cell membranes of OV-10 63 cancers; however, after in vivo treatment with AN-152, LH-RH recept or-binding sites were not detectable and EGF receptors were reduced in number. The growth of UCI-107 ovarian cancers was not inhibited by AN -152. Conclusions: In nude mice bearing LH-RH receptor positive OV-106 3 epithelial ovarian cancers, systemic administration of AN-152 is les s toxic and inhibits tumor growth better than equimolar doses of doxor ubicin.