Targeted cytotoxic luteinizing hormone releasing hormone (LH-RH) anlalogs inhibit growth of estrogen independent MXT mouse mammary cancers in vivo by decreasing cell proliferation and inducing apoptosis.
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 present on MXT tumor samples of control untreated mice, but no binding sites for LH-RH could be found on tumor membranes after treatment with the cytotoxic LH-RH analogs. The results suggest that these powerful targeted cytotoxic LH-RH analogs could be considered for treatment of human mammary cancers having receptors for LH-RH.
Szepeshazi
K
K
Veterans Affairs Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70146, USA.
Schally
A V
AV
Nagy
A
A
Halmos
G
G
Groot
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D004967:Estrogens; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D011758:Pyrroles / Q000494:pharmacology; D011966:Receptors, LHRH / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D004967:Estrogens; D011758:Pyrroles; D011966:Receptors, LHRH; C098751:AN 204; D007987:Gonadotropin-Releasing Hormone; D004317:Doxorubicin