Inhibition of growth of MCF-7 MIII human breast carcinoma in nude mice by treatment with agonists or antagonists of LH-RH.
Human breast carcinoma (MCF-7 MIII), which exhibits an estrogen-independent but estrogen-responsive phenotype, was xenografted in 8-9-week-old intact female athymic nude mice without estrogen supplementation. In this model, we investigated inhibitory effects of the modern luteinizing hormone-releasing hormone (LH-RH) antagonist SB-75 and the agonist D-Trp6-LH-RH. The analogs were administered in the form of sustained delivery systems (microcapsules and microgranules). In the first experiment, treatment lasted 10 weeks. After 9 weeks of treatment, a significant inhibition of tumor volume was first found only in the group treated with SB-75, but the final tumor volume was significantly suppressed both by D-Trp6-LH-RH and SB-75. In the second experiment, treatment was started 70 days after tumor transplantation and was continued for 6 weeks. Chronic treatment with SB-75 or D-Trp6-LH-RH appeared to completely arrest tumor growth as measured by tumor volume, percentage change in tumor volume, and tumor weight. Serum estradiol was suppressed to undetectable levels and LH levels were also diminished. Histologically, the regressive changes in the treated tumors were due to the enhancement of apoptosis (programmed cell death) of tumor cells. Membrane receptor assays showed that LH-RH binding sites were down-regulated in tumor cells after treatment with SB-75 or D-Trp6-LH-RH. The results indicate that the antagonist SB-75, released from sustained delivery systems, can inhibit the growth of MCF-7 MIII tumors as effectively as the agonist D-Trp6-LH-RH, but more rapidly. In view of its immediate blockade of the pituitary-gonadal axis and the absence of side effects, the LH-RH antagonist SB-75 might be considered as a possible new hormonal agent for the treatment of breast cancer.
Yano
T
T
Endocrine, Polypeptide and Cancer Institute, Veterans Administration Medical Center, New Orleans, LA 70146.
Korkut
E
E
Pinski
J
J
Szepeshazi
K
K
Milovanovic
S
S
Groot
K
K
Clarke
R
R
Comaru-Schally
A M
AM
Schally
A V
AV
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000453:epidemiology / Q000473:pathology*; D004967:Estrogens; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D015994:Incidence; D007279:Injections, Subcutaneous; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D007986:Luteinizing Hormone / Q000097:blood; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D010052:Ovariectomy; D014183:Transplantation, Heterologous; D017329:Triptorelin Pamoate / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000637:transplantation
D004967:Estrogens; D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone; D007334:Insulin-Like Growth Factor I; D007986:Luteinizing Hormone; C062876:cetrorelix