Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone.

Abstract

Metal Superagonist analogues of luteinizing hormone (LH)-releasing hormone (LH-RH), <Glu-His-Trp-Ser-Tyr-GlyLeu-Arg-Pro-Gly-NH2 (where <Glu is pyroglutamic acid), have been reported to be of value in treating patients with certain sex hormone-dependent tumors, such as breast and prostatic cancers (1-3). Inhibition of breast or prostate tumor growth during therapy with LH-RH analogs is mediated mainly by the suppression of gonadal steroid secretion (3-5), but direct effects of these peptides on tumor cells may also be involved (6). Human breast cancer specimens and some breast cancer cell lines contain binding sites for LH-RH (6-10), and the growth of some breast cancer cell lines can be inhibited by an LH-RH agonist (7) or antagonist (8 (14). In addition to the use of the combination of LH-RH analogues and cytotoxic agents, such combined therapy could be provided by treatment with highly potent agonistic or antagonistic analogues of LH-RH that contain cytotoxic moieties. Such analogues could exert the effect of LH-RH agonists or antagonists and, at the same time, act as chemotherapeutic agents targeted to the tumor cells by their peptide portions for which binding sites are present on the cell membranes. In the accompanying paper (15) The methyl ester of 6-aminohexanoic acid (Ahx-OMe) was purchased from American Dynamics (South Plainfield, NJ). L-2,3-Diaminopropionic acid (A2pr) was obtained from Calbiochem-Behring, DL-A2pr, DL-and L-2,4-diaminobutyric acid (A2bu), <Glu, salicylaldehyde, 5-chlorosalicylaldehyde, pyridoxal, pyridoxal 5'-phosphate, Cu(OAc)2, Ni(OAc)2, and K2PtCl4 were purchased from Aldrich. Diamino acids were derivatized (Boc2A2pr, Boc2A2bu, Z2A2pr, and Z2A2bu, where Z is benzyloxycarbonyl) by published methods (19).Metal Complexes of Hydroxy Oxo Compounds. Bis(salicylaldehydato)nickel(II), nickel(II) complexes of related hydroxy oxo compounds, and the corresponding copper(II) complexes were prepared according to the methods described previously (20).Dipeptides. Boc2A2pr-Ahx and Boc2A2bu-Ahx were obtained from the appropriate di-Boc-amino acid and Ahx-OMe by mixed anhydride coupling followed by saponification.

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

“…The cytotoxic compounds included alkylating agent melphalan, DNA strandbreaker cross-linking agent cisplatin, antimetabolite methotrexate and anthracycline derivative 2-(hydroxymethyl)anthraquinone. 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).…”

“…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).…”

Cytotoxic analogs of luteinizing hormone-releasing hormone containing doxorubicin or 2-pyrrolinodoxorubicin, a derivative 500-1000 times more potent.

“…A more specific local delivery by targeting of highly active cytotoxic agents to tumor cells, based on Paul Ehrlich's idea of "magic bullets" (1), offers an approach that might overcome these drawbacks. Macromolecules such as monoclonal antibodies, proteins, or peptide hormones for which specific receptors are located on cancerous cells, have been widely used as carriers for conjugation to suitable cytotoxic radicals (2)(3)(4)(5)(6)(7)(8)(9). The presence of receptors for luteinizing hormone-releasing hormone (LH-RH) on membranes of various tumor cells makes analogs of LH-RH, which can bind to these receptors, excellent choices as carrier molecules (3).…”

Peptide-Based Cancer-Targeted DDS and Molecular Imaging

“…96,97) Based on the native LHRH peptide, short LHRH peptide analogues were developed as tumor-specific ligands. 98,99) LHRH peptide analogues linked to anticancer agents via ester bonds were also synthesized and improved the accumulation of the linked agents. As an example, a clinical trial was conducted of the peptide [D-Lys 6 ] LHRH linked to DOX (AEZS-108).…”