Elsevier

Life Sciences

Volume 72, Issue 21, 11 April 2003, Pages 2305-2320
Life Sciences

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New approaches to treatment of various cancers based on cytotoxic analogs of LHRH, somatostatin and bombesin

https://doi.org/10.1016/S0024-3205(03)00113-9Get rights and content

Abstract

The development of targeted cytotoxic analogs of hypothalamic peptides for the therapy of various cancers is reviewed and various oncological studies on experimental tumors are summarized. Novel therapeutic modalities for breast, prostate and ovarian cancer consist of the use of targeted cytotoxic analogs of LH-RH containing doxorubicin (DOX) or 2-pyrrolino-DOX. The same radicals have been incorporated into cytotoxic analogs of somatostatin which can be also targeted to receptors for this peptide in prostatic, mammary, ovarian, renal and lung cancers, brain tumors and their metastases. A targeted cytotoxic analog of bombesin containing 2-pyrrolino-DOX has also been synthesized and successfully tried in experimental models of prostate cancer, small cell lung carcinoma and brain tumors. The development of these new classes of peptide analogs should lead to a more effective treatment for various cancers.

Introduction

Chemotherapy is the main modality for systemic treatment of advanced or metastatic cancers and can also be applied as adjuvant to surgery and radiotherapy [7]. However, cancer chemotherapy is restricted by the toxicity of chemotherapeutic drugs and a more selective delivery of the cytotoxic agents to the primary tumors and their metastases would allow a dose escalation and reduce the peripheral toxicity.

Targeted chemotherapy represents a modern oncological strategy designed to improve the effectiveness of cytotoxic drugs and decrease peripheral toxicity. The receptors for peptide hormones on tumor cells can serve as targets for peptide ligands that can be linked to various cytotoxic agents. During the past 10 years we have synthesized and evaluated cytotoxic analogs of LHRH, somatostatin, and bombesin that can be targeted to various tumors [39], [41], [42], [43], [44], [56]. In this presentation we will review the antitumor effects of our cytotoxic analogs in experimental cancer models.

Section snippets

Cytotoxic analogs of luteinizing hormone-releasing hormone (LHRH)

In the past 30 years, several thousand analogs of LHRH have been synthesized [24], [53], [54], [55], [57]. Agonistic analogs have found important clinical applications in gynecology and oncology. Potent antagonists of LHRH such as Cetrorelix have been also synthesized [53], [57].

The actions of LHRH analogs are mediated by receptors for LHRH found on the pituitary gonadotrophs [12], [53], [54], [55], [57]. The down-regulation of LHRH receptors, produced by sustained administration of LHRH

Cytotoxic somatostatin analogs

Potent octapeptide analogs of somatostatin including octreotide (Sandostatin) [2] and vapreotide (RC-160) [6] have been developed during the past 20 years. Somatostatin and its octapeptide analogs exert their effects through specific membrane receptors. Five distinct receptor subtypes (sst1–5) have been cloned and characterized [45]. Native somatostatin shows similar high affinity to sst1–5, but the synthetic octapeptides such as RC-160 and octreotide bind preferentially to sst2 and sst5.

Cytotoxic analogs of bombesin/gastrin releasing peptide

Gastrin-releasing peptide (GRP) has 27-amino acids and its carboxyl-terminal decapeptide is similar to that of tetradecapeptide bombesin [63]. GRP is widely distributed in lung and gastrointestinal tract, is produced in SCLC, breast, prostatic and pancreatic cancer and functions as growth factor [9], [53], [63]. Four receptor subtypes associated with the bombesin-like peptide family have been identified [9], [25], [39], [53].

The finding that bombesin or GRP can function as an autocrine growth

Strategies for therapy

Since the peptide receptors and mRNAs of receptor subtypes are variably expressed in diverse cancers, a careful determination of receptors and their subtypes in tumor tissue is required before therapy with cytotoxic analogs [53], [54]. Thus, biopsy samples of primary cancers and in some cases their metastases, should be subjected to ligand competition assays, Western Blots, and/or RT-PCR analyses for messenger ribonucleic acid (mRNA) expression of receptor subtypes. The tumors and their

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