Chemotherapy targeted to cancers through tumoral hormone receptors

doi:10.1016/j.tem.2004.07.002

Trends in Endocrinology & Metabolism

Volume 15, Issue 7, September 2004, Pages 300-310

https://doi.org/10.1016/j.tem.2004.07.002 Get rights and content

Work on cytotoxic analogs of luteinizing hormone-releasing hormone (LH-RH), somatostatin and bombesin, designed for targeting chemotherapy to peptide receptors on various cancers, is reviewed here as the project is at advanced stages of development and clinical trials are pending. 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 can be used for the treatment of prostatic, breast, ovarian and endometrial cancers and melanomas. AN-201 was also incorporated into the cytotoxic analog of somatostatin, AN-238, which can be targeted to receptors for somatostatin in prostatic, renal, mammary, ovarian, gastric, colorectal and pancreatic cancers as well as glioblastomas and lung cancers, suppressing the growth of these tumors and their metastases. A cytotoxic analog of bombesin AN-215, containing 2-pyrrolino-DOX, was likewise synthesized and successfully tested in experimental models of prostate cancer, small cell lung carcinoma, gastrointestinal cancers and brain tumors expressing receptors for bombesin/gastrin-releasing peptide. This new class of targeted cytotoxic peptide analogs might provide a more effective therapy for various cancers.

Section snippets

Receptors for LH-RH

The actions of LH-RH are mediated by specific G protein-coupled receptors for LH-RH present on the plasma membranes of the pituitary gonadotrophs 20, 23. Binding of LH-RH to its receptors causes a microaggregation of receptors, complex formation and internalization. Sustained stimulation of the pituitary by chronic administration of LH-RH or its agonists produces ‘down-regulation’ (a reduction in number) of pituitary receptors for LHRH and suppression of circulating levels of LH and sex

Receptors for somatostatin

Various analogs of the neuropeptide somatostatin, including octreotide (Sandostatin), vapreotide (RC-160) and lanreotide have been developed for therapeutic purposes 8, 15, 18, 19, 21, 22. Somatostatin and its octapeptide analogs exert their effects through G-protein coupled receptors 15, 42. At least five distinct receptor subtypes (sst_1–5) have been cloned and characterized [42]. The synthetic octapeptides, such as octreotide, bind preferentially to sst₂ and sst₅ and have moderate affinity

Cytotoxic analogs of bombesin or gastrin-releasing peptide

Gastrin-releasing peptide (GRP) is a mammalian homologue of amphibian bombesin and its carboxyl-terminal decapeptide is similar to that of bombesin 15, 16, 19, 22. GRP is widely distributed in the brain, lungs and gastrointestinal tract and functions as a growth factor. Four receptor subtypes associated with the bombesin-like peptide family have been identified 15, 16, 19, 22. The bombesin/GRP receptor subtype 1 has been detected on a wide variety of human malignancies including SCLC and

Other approaches to targeted therapy

Recently Leuschner et al. [71] described the development of a targeted cytotoxic LH-RH analog consisting of Hecate, a 23 amino acid amphipathic lytic peptide conjugated to LH-RH itself to form a 33-amino acid peptide (LHRH-Hecate). The conjugate showed a high cytotoxicity on LH-RH receptor-expressing prostate cancer cells, such as LnCaP, PC-3 and DU-145. The in vivo administration of LH-RH-Hecate conjugate inhibited growth of PC-3 prostatic cancer in nude mice [71].

It has been also demonstrated

Conclusion

The origins of chemotherapy, concepts of drug targeting and targeted therapies based on immunotoxins and monoclonal antibodies have been briefly discussed here. Design, synthesis and preclinical testing of cytotoxic analogs of LH-RH, somatostatin and bombesin/GRP for chemotherapy targeted to cancers through tumoral receptors were extensively reviewed as this project is at more advanced stages of development than work on other peptides. The concept of targeting to receptors extends to

Acknowledgements

Work described in this article was supported by the medical research service of the Veterans Affairs Department and grants from Zentaris Gmbh (Frankfurt on Main, Germany) to Tulane University School of Medicine (to A.V.S.).

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Trends in Endocrinology & Metabolism

Featured reviewChemotherapy targeted to cancers through tumoral hormone receptors

Section snippets

Receptors for LH-RH

Receptors for somatostatin

Cytotoxic analogs of bombesin or gastrin-releasing peptide

Other approaches to targeted therapy

Conclusion

Acknowledgements

Front. Neuroendocrinol.

Life Sci.

Trends Endocrinol. Metab.

Rec. Prog. Horm. Res.

J. Urol.

Am. J. Obstet. Gynecol.

Am. J. Obstet. Gynecol.

Cancer Lett.

Front. Neuroendocrinol.

J. Urol.

Eur. J. Cancer

Regul. Pept.

Curr. Opin. Genet. Dev.

Pharmacol. Ther.

Beyond DNA cross-linking: history and prospects of DNA-targeted cancer treatment-fifteenth Bruce F. Cain Memorial Award Lecture

Cancer Res.

Toxicological testing of cytotoxic drugs

Int. J. Oncol.

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

Eur. J. Endocrinol.

Targeted toxin therapy for the treatment of cancer

J. Natl. Cancer Inst.

Accumulation of a recombinant immunotoxin in a tumor in vivo: fewer than 1000 molecules per cell are sufficient for complete responses

Cancer Res.

Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer

J. Clin. Oncol.

Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2

N. Engl. J. Med.

Bevacizumab (a monoclonal antibody to vascular endothelial growth factor) prolongs survival in first-line colorectal cancer (CRC): Results of a phase III trial of bevacizumab in combination with bolus IFL (irinotecan, 5-fluorouracil, leucovorin) as first-line therapy in subjects with metastatic CRC

(ASCO) American Society of Clinical Oncology Meeting

Therapeutic cancer targeting peptides

Biopolymers

Cytotoxic analogs of luteinizing hormone-releasing hormone (LHRH); a new approach to targeted chemotherapy

Drugs Future

Targeted cytotoxic somatostatin analogs: a modern approach to the therapy of various cancers

Drugs Future

The actions of LH-RH agonists, antagonists, and cytotoxic analogs on the LH-RH receptors on the pituitary and tumors

Peptide receptors as molecular targets for cancer diagnosis and therapy

Endocr. Rev.

Presence and characteristics of receptors for [D-Trp6]-luteinizing hormone-releasing hormone and epidermal growth factor in human ovarian cancer

Int. J. Oncol.

Receptor mediated antiproliferative effects of the cytotoxic LHRH agonist AN-152 in human ovarian and endometrial cancer cell lines

Int. J. Oncol.

Locally expressed LHRH receptors mediate the oncostatic and antimetastatic activity of LHRH agonists on melanoma cells

J. Clin. Endocrinol. Metab.

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

Proc. Natl. Acad. Sci. U. S. A.

Effective treatment of advanced estrogen-independent MXT mouse mammary cancers with targeted cytotoxic LH-RH analogs

Breast Cancer Res. Treat.

Featured review
Chemotherapy targeted to cancers through tumoral hormone receptors

Presence and characteristics of receptors for [D-Trp⁶]-luteinizing hormone-releasing hormone and epidermal growth factor in human ovarian cancer