Inhibition of growth of MCF-7 MIII human breast carcinoma in nude mice by treatment with agonists or antagonists of LH-RH

Abstract

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.

Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

“…The expression of mRNA for LHRH receptors was also found in PC-82, DU-145 and LNCaP tumors and in most human prostate cancer specimens (31,33,34). Several investigators reported the presence of LHRH receptors in various human mammary carcinoma cell lines including MCF-7 and MDA-MB-231 (35)(36)(37). We detected high-affinity LHRH binding sites in more than 50% of human breast cancer samples (38).…”

Inhibition of growth of human malignant glioblastoma in nude mice by antagonists of bombesin/gastrin-releasing peptide

“…The levels of c-jun oncogene were also investigated in tumors from mice treated with RC-3095 and RC-3940-II, but no signi®cant e ect was found as compared with the controls (data not shown). We then cultured U-87MG cells for 18 h in vitro as described previously (Pinski et al, 1994d), except that the tissue culture medium contained 2.5% v/v heat-inactivated, dextran-coated, charcoal-treated fetal bovine serum (Yano et al, 1992). Subsequently, cells were exposed to 10 77 M GRP(14 ± 27) for 1 h. The mRNA levels of c-fos oncogene were assessed by RT ± PCR at various time periods after the exposure to GRP(14 ± 27).…”

Anti-gonadotrophin releasing hormone antibodies inhibit the growth of MCF7 human breast cancer xenografts

“…Agonists and antagonists of luteinizing hormone releasing hormone (LHRH) have been shown to be inhibitory to the growth of MCF7-MIII xenografts, and to reduce serum levels of both E 2 and LH in treated animals (Yano et al, 1992). Passive infusion of anti-GnRH Ab had a similar effect resulting in suppression of serum E 2 to very low levels, and also reducing serum LH levels compared to those in controls.…”