melphalan and 2-(hydroxymethyl)anthraquinone

Five hexapeptide and heptapeptide analogs of luteinizing hormone-releasing hormone (LH-RH) were synthesized for use as carriers for cytotoxic compounds. These short analogs were expected to enhance target selectivity of the antineoplastic agents linked to them. Native LH-RH-(3-9) and LH-RH-(4-9) containing D-lysine and D-ornithine at position 6 were amidated with ethylamine and acylated on the N terminus. The receptor-binding affinity of one hexapeptide carrier AJ-41 (Ac-Ser-Tyr-D-Lys-Leu-Arg-Pro-NH-Et) to human breast cancer cell membranes was similar to that of [D-Trp6]LH-RH. Alkylating nitrogen mustards (melphalan, Ac-melphalan), anthraquinone derivatives including anticancer antibiotic doxorubicin, antimetabolite (methotrexate), and cisplatin-like platinum complex were linked to these peptides through their omega-amino group at position 6. The hybrid molecules showed no LH-RH agonistic activity in vitro and in vivo but had nontypical antagonistic effects on pituitary cells in vitro at the doses tested. These analogs showed a wide range of receptor-binding affinities to rat pituitaries and cell membranes of human breast cancer and rat Dunning prostate cancer. Several of these conjugates exerted some cytotoxic effects on MCF-7 breast cancer cell line.

Topics: Amino Acid Sequence; Animals; Anthraquinones; Antineoplastic Agents; Breast Neoplasms; Cell Membrane; Cell Survival; Cisplatin; Doxorubicin; Female; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Male; Melphalan; Methotrexate; Molecular Sequence Data; Oligopeptides; Orchiectomy; Pituitary Gland; Prostatic Neoplasms; Rats; Receptors, LHRH; Structure-Activity Relationship; Tumor Cells, Cultured