Effective treatment of advanced estrogen–independent MXT mouse mammary cancers with targeted cytotoxic LH–RH analogs

Abstract

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.