Effect of treatment with LHRH analogs containing cytotoxic radicals on the binding characteristics of receptors for luteinizing-hormone-releasing hormone in MXT mouse mammary carcinoma.
Binding capacities and apparent dissociation constants of receptors for luteinizing-hormone-releasing hormone (LHRH) were investigated in estrogen-independent MXT mammary cancers of untreated mice and after in vivo treatment with agonistic or antagonistic analogs of LHRH containing cytotoxic radicals: AJ-04 (agonist [D-Lys6]LHRH linked to methotrexate), T-98-([D-Lys6]LHRH coupled to glutaryl-2-(hydroxmethyl)anthraquinone (G-HMAQ)) and T-121/B (LHRH antagonist T-147 containing two residues of G-HMAQ), which induced tumor growth inhibition. The effects were compared to LHRH agonist [D-Trp6]LHRH and carriers [D-Lys6]LHRH, LHRH antagonist T-147, as well as to methotrexate, G-HMAQ and surgical bilateral overiectomy. Analysis of the binding data revealed that in control tumors the interaction of 125I-[D-TRP6]LHRH was consistent with the presence of one class of saturable, specific, noncooperative, high-affinity and low-capacity binding sites. Chronic treatment of mice bearing MXT tumors with LHRH analogs AJ-04 and T-121/B carrying cytotoxic radicals, but not with T-98 produced significant down-regulation of membrane receptors for LHRH. The largest decrease in dissociation binding constant and Bmax of receptors for LHRH was also found in animals treated with T-121/B. Specific, high affinity binding of 125I-labelled epidermal growth factor (EGF) was detected in the membranes from control and treated MXT tumors. Treatment with cytotoxic LHRH analogs, AJ-04, T-98 and especially with T-121/B, reduced maximal binding capacity of EGF receptors. Our results indicate that LHRH analogs carrying cytotoxic radicals retain their hormonal activity and inhibit tumor growth while inducing down-regulation of LHRH receptors. In addition, probably both components of the cytotoxic LHRH analog, peptide carriers and cytotoxic radicals, reduce the binding capacity of EGF receptors, which might be useful in the treatment of breast cancer.
Milovanovic
S R
SR
Endocrine, Polypeptide and Cancer Institute, Veterans Administration Medical Center, New Orleans, Louisiana.
Monje
E
E
Szepeshazi
K
K
Radulovic
S
S
Schally
A
A
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D004337:Drug Carriers; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005609:Free Radicals / Q000633:toxicity; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D007457:Iodine Radioisotopes; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000648:ultrastructure; D008727:Methotrexate / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D011966:Receptors, LHRH / Q000187:drug effects / Q000378:metabolism*; D017329:Triptorelin Pamoate / Q000494:pharmacology
D000970:Antineoplastic Agents; D004337:Drug Carriers; D005609:Free Radicals; D007457:Iodine Radioisotopes; D011966:Receptors, LHRH; D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone; D066246:ErbB Receptors; D008727:Methotrexate