Use of analogs of peptide hormones conjugated to cytotoxic radicals for chemotherapy targeted to receptors on tumors.

Abstract

Specific receptors for luteinizing hormone-releasing hormone (LH-RH), somatostatin, bombesin, and other peptides are found on various cancers. We review the development of cytotoxic analogs of LH-RH, somatostatin, and bombesin/gastrin releasing peptide (GRP) designed for targeting chemotherapy to peptide receptors on various cancers. Cytotoxic analogs of LH-RH, AN-152 and AN-207, containing doxorubicin (DOX) or 2-pyrrolino-DOX (AN-201), respectively, target LH-RH receptors and may be used for the treatment of prostatic and urinary bladder (urothelial), breast, ovarian and endometrial cancers, non-Hodgkin's lymphomas, melanomas, and renal cell carcinomas. DOX and AN-201 have also been incorporated into the cytotoxic analogs of somatostatin, AN-162 and AN-238, respectively, which are targeted to receptors for somatostatin in prostatic, mammary, ovarian, gastric, renal, colorectal and pancreatic cancers, non-Hodgkin's lymphomas, as well as glioblastomas and lung cancers. They are found to suppress the growth of these tumors and their metastases. A cytotoxic analog of bombesin/GRP, AN-215, containing 2-pyrrolino-Dox, has also been synthesized and shown to inhibit growth of various human cancer lines expressing receptors for bombesin/GRP. The toxicity, pharmacokinetics and maximum tolerated doses of AN-152 were assessed in a phase I clinical trial in women with ovarian or endometrial cancer. Disease stabilization and objective responses were found. Analog AN-152 is now in phase II clinical trials. Phase I/II studies with AN-152 in men with hormone-independent relapsed prostate cancer and patients with pancreatic and bladder cancers are pending. Targeted cytotoxic peptide analogs could provide a more efficacious and less toxic therapy for various cancers.

• Authors: Andrew V Schally, Jorg B Engel, Gunter Emons, Norman L Block, Jacek Pinski
• Journal: Current drug delivery (Curr Drug Deliv) Vol. 8 Issue 1 Pg. 11-25 (Jan 2011) ISSN: 1875-5704 [Electronic] United Arab Emirates
• PMID: 21034424 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Review)

Chemical References

• Antineoplastic Agents
• Peptide Hormones
• Receptors, Peptide

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Clinical Trials as Topic
• Humans
• Molecular Targeted Therapy (methods)
• Neoplasms (drug therapy, metabolism)
• Peptide Hormones (chemistry, pharmacology, therapeutic use)
• Receptors, Peptide (metabolism)