Growth inhibition of estrogen independent MXT mouse mammary carcinomas in mice treated with an agonist or antagonist of LH-RH, an analog of somatostatin, or a combination.
Female BDF1 mice inoculated with MXT (3.2) estrogen independent mouse mammary carcinoma were treated for three weeks with microcapsules of the luteinizing hormone-releasing hormone (LH-RH) agonist [D-Trp6]LH-RH, the antagonist SB-75, the somatostatin analog RC-160, or combinations. The lack of estrogen dependence of the tumor was proved by bilateral surgical ovariectomy, which had no effect. In two experiments, treatment with 25 micrograms/day doses of each analog alone resulted in a significant inhibition of tumor growth as shown by a 40-53% inhibition of tumor volumes, 38-43% decrease in tumor weights, and histological signs of tumor regression. However, the combination of SB-75 or [D-Trp6]LH-RH with somatostatin analog RC-160 caused greater reduction of tumor volume (68 and 61%) or tumor weights (59 and 56%), than single analogs, and histologically the occurrence of apoptosis and decrease in AgNOR numbers was more pronounced in the groups receiving combination therapy. Specific binding sites for [D-Trp6]LH-RH, EGF, and IGF-I were demonstrated in the tumor membranes. The binding capacity of LH-RH receptors was decreased by treatment with the analogs, the greatest down-regulation being caused by combination therapy. A significant decrease in EGF binding capacity was observed after treatment with the LH-RH analogs, alone or especially in combination with somatostatin analog RC-160. The combination of these analogs also caused a reduction in IGF-I receptors. The finding that LH-RH agonists and antagonists and somatostatin analogs inhibit the growth of estrogen independent mammary tumors, and that combinations are more effective than single analogs, might be of practical importance in human breast cancer therapy.
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA 70146.
K
K
Szepeshazi
S
S
Milovanovic
K
K
Lapis
K
K
Groot
A V
AV
Schally
D000595:Amino Acid Sequence; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D004339:Drug Compounding; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008325:Mammary Neoplasms, Experimental / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000032:analysis; D011956:Receptors, Cell Surface / Q000032:analysis; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017329:Triptorelin Pamoate
D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; D017329:Triptorelin Pamoate; C051458:vapreotide; D007987:Gonadotropin-Releasing Hormone; D013004:Somatostatin; C062876:cetrorelix