Abstract
Tumor inhibitory action and the optimal dosage regimens of highly potent targeted cytotoxic luteinizing hormone releasing hormone (LH-RH) analogs containing doxorubicin (DOX) or 2-pyrrolino-DOX (AN-201) were tested in female BDF mice bearing estrogen independent MXT mouse mammary cancers. The effects were compared to those obtained with the cytotoxic radicals DOX or AN-201 alone. Analog AN-207, formed by linking 2-pyrrolino-DOX to [D-Lys6]LH-RH, and analog AN-152, produced by conjugation of DOX to the same carrier, given i.p. as a single injection or repeatedly 2 days apart at their maximum tolerated doses (MTDs) resulted in a 89-93% inhibition of tumor growth. Equimolar amounts of the cytotoxic radicals were toxic. AN-207 and AN-152 likewise had stronger tumor inhibitory effects than their respective cytotoxic radicals AN-201 or DOX alone, when compared at the lower doses corresponding to MTDs of the radicals. Histological evaluation indicated that decreased cell proliferation (shown by mitotic index and AgNOR counts) as well as increased apoptosis (demonstrated by histological and biochemical methods) both contributed to tumor suppression caused by the cytotoxic hormone analogs. Specific, high-affinity LH-RH receptors were pr...Continue Reading
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