Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups.

Abstract

In an attempt to produce better cytotoxic analogues, chemotherapeutic antineoplastic radicals including an alkylating nitrogen mustard derivative of D-phenylalanine (D-melphalan), reactive cyclopropane, anthraquinone derivatives [2-(hydroxymethyl)anthraquinone and the anticancer antibiotic doxorubicin], and an antimetabolite (methotrexate) were coupled to suitably modified agonists and antagonists of luteinizing hormone-releasing hormone (LH-RH). Analogues with D-lysine' and D-ornithine6 or N8-(2,3-diaminopropionyl)-D-lysine and N8-(2,3-diaminopropionyl)-D-ornithine were used as carriers for one or two cytotoxic moieties. The enhanced biological activities produced by the incorporation of D amino acids into position 6 of the agonistic analogues were further increased by the attachment of hydrophobic cytotoxic groups, resulting in compounds with 10-50 times higher activity than LH-RH. Most of the monosubstituted agonistic analogues showed high affinities for the membrane receptors of human breast cancer cells, while the receptor binding afnities of peptides containing two cytotoxic side chains were lower. Chemotherapy has been, for many decades, one of the main approaches for the treatment of malignant neoplasms. Despite the development of modem, more specific cytotoxic drugs, their nonselective action on cells other than cancerous ones remains a major problem. A recent modality for the treatment of hormone-sensitive tumors is based on the use of agonists and antagonists of luteinizing hormone-releasing hormone (LH-RH) (1). Some LH-RH agonists substituted in position 6, 10, or both are much more active than LH-RH and also possess prolonged activity (1-3). Changes in positions 1, 2, 3, and 6 and occasionally in positions 5 and 10 of the LH-RH molecule lead to the formation of powerful antagonists (1-4), which inhibit the release of LH and folliclestimulating hormone from the pituitary, create a state of sex-steroid deprivation, and thus have potential therapeutic applications in the treatment of some hormone-dependent cancers such as those of prostate and breast (1, 5).Ideal anticancer drugs would theoretically be those that eradicate cancer cells without harming normal cells. Some hormonal peptide analogues carrying antineoplastic agents could be used for endocrine therapy and at the same time for targeted chemotherapy of cancers that possess receptors for their peptide moieties on tumor cell membranes.

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

“…Complexes of heavy metals such as Cu and Zn were also incorporated by sophisticated chemistry (20). In some of these early conjugates, DNA intercalating antibiotic doxorubicin (DOX), the most widely used anticancer agent, was linked to LHRH analogs using a glutaric acid spacer which formed carboxamide bonds between the daunosamine nitrogen of DOX and the -amino group of the D-Lys 6 moiety of the carrier (21). Unfortunately, the antiproliferative activity of DOX within these hybrids was greatly reduced due to the modification by the linkage.…”

“…It turned out that even bulky molecules could be linked to the -amino group of the D-Lys 6 moiety without significant loss of the high binding affinity of the peptide portion to receptors for LHRH. This bulk tolerance was exploited in our attempts to create cytotoxic LHRH hybrids in which diverse cytotoxic radicals were attached covalently to the D-Lys side-chain of the LHRH carrier agonists or antagonists (21,47). The cytotoxic compounds included alkylating agent melphalan, DNA strandbreaker cross-linking agent cisplatin, antimetabolite methotrexate and anthracycline derivative 2-(hydroxymethyl)anthraquinone.…”

“…The 'magic bullet' approach was utilized by us for the synthesis of a large number of cytotoxic analogs of hypothalamic peptides (12,(19)(20)(21)(22). These consisted of diverse hormonal analogs, mostly of LHRH, conjugated to a variety of chemotherapeutic agents.…”

“…These consisted of diverse hormonal analogs, mostly of LHRH, conjugated to a variety of chemotherapeutic agents. The high specificity of peptide receptors was utilized in an attempt to deliver these agents to the tumor cells where they might exert their cytotoxic effects (19)(20)(21)(22). It was hoped that such hybrids could selectively destroy classes of cells containing specific receptors for several peptide hormones found on various cancer cells and serve as specific therapeutic agents for cancer treatment (12).…”

Harnessing Preclinical Molecular Imaging to Inform Advances in Personalized Cancer Medicine

“…One notable example is the radiolabeled thymidine analog, 39-deoxy-39-18 F-fluorothymidine ( 18 F-FLT), which is a substrate for thymidine kinase 1-the rate-limiting enzyme in the salvage of thymidine and deoxyuridine. As thymidine kinase 1 expression and activity peak during the S phase of the cell cycle (47), labeled thymidine incorporation is commonly used for monitoring cell proliferation (49,50).…”