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were initially developed to block growth hormone (GH) secretion from the pituitary glands, leading to inhibition of insulin-like growth factor I (IGF-I) production in the liver and other tissues (1-6). The reduction in the levels of serum IGF-I could inhibit the proliferation of various cancers dependent on IGF-I, in view of involvement of this growth factor and of IGF-II, which is GH independent, in malignant transformation of cells, tumor progression, and metastasis (1-3). GHRH antagonists were shown to effectively inhibit the in vivo growth of various experimental human cancers, including osteosarcomas, mammary, ovarian and prostatic cancers, renal adenocarcinomas, small-cell lung cancer (SCLC) and non-SCLC, pancreatic and colorectal carcinomas, and malignant gliomas (7-17). The proliferation of some of these human cancers in vitro was also suppressed by GHRH antagonists (7-10, 12-14, 16-18). This finding and the reduction in the concentration of IGF-I and IGF-II and the suppression of the gene expression of IGF-I and -II in the tumors suggested that GHRH antagonists, in addition to indirect action mediated by inhibition of GH-IGF-I axis, might exert direct effects on tumor growth through specific yet-to-be-identified GHRH receptors (3,19).The GHRH receptor is a G-protein-coupled transmembrane receptor found predominantly in the pituitary gland, and its mRNA has also been detected in rat placenta, kidney, testis, hypothalamus, and the gastrointestinal tract (20-23). Receptors for other GHRH-related peptides, such as vasoactive intestinal peptide (VIP) and secretin, also belong to the G-protein-linked superfamily and show homology to GHRH receptor proteins (23). Although VIP receptors have been detected in various tumors and could be involved in the regulation of tumor growth (21,(24)(25)(26), recent work showed that the antiproliferative effect of GHRH antagonists is exerted through a mechanism independent of VIP receptors (27). When primers for human GHRH (hGHRH) receptor mRNA were used (27), no expression of mRNA was found in LNCaP human prostatic and MiaPaCa-2 human pancreatic cancer cells (27), in accordance with an earlier report on ovarian tumors (28). In addition, specific binding sites for radioligand [His 1 , 125 I-Tyr 10 ,Nle 27 ]hGHRH(1-32)NH 2 could not be detected in human cancers (14,17,27), although this radioligand is widely used for the characterization of pituitary GHRH receptors (29-31). These observations indicate that peptide receptors on human tumors that respond to our GHRH antagonists should be different from the classic pituitary-type GHRH receptors.In this study, we report the presence of high-affinity binding sites for GHRH antagonists on CAKI-1 human renal cell carcinoma (RCC). The binding characteristics were investigated by ligand competition assays, using 125 I-labeled GHRH antagonist JV-1-42 as a specific radioligand. These binding sites appear to be isoforms of hGHRH receptor, as demonstrated by reverse transcription (RT)-PCR, and are also distinct from the VIP receptors. In a...

The use of peptide analogs in the therapy of prostate cancer is reviewed. The preferred primary treatment of advanced androgen‐dependent prostate cancer is presently based on the use of depot preparations of LH‐RH agonists. This treatment is likewise recommended in patients with rising PSA levels after surgery or radiotherapy. LH‐RH agonists with or without antiandrogens can be also utilized prior to or following various local treatments in patients with clinically localized prostate cancer and at high risk for disease recurrence. LH‐RH antagonists like Cetrorelix are in clinical trials. However, most patients with advanced prostatic carcinoma treated by any modality of androgen deprivation eventually relapse. Treatment of relapsed androgen‐independent prostate cancer remains a major challenge, but new therapeutic modalities are being developed based on antagonists of growth hormone‐releasing hormone (GH‐RH) and bombesin, which inhibit growth factors or their receptors. Another approach consists of cytotoxic analogs of LH‐RH, bombesin, and somatostatin containing doxorubicin or 2‐pyrrolinodoxorubicin, which can be targeted to receptors for these peptides found in prostate cancers and their metastases. These cytotoxic analogs inhibit growth of experimental androgen‐dependent or ‐independent prostate cancers and reduce the incidence of metastases. A rational therapy with peptide analogs could be selected on the basis of receptors present in biopsy samples. The approaches based on peptide analogs should result in a more effective treatment for prostate cancer. Prostate 45:158–166, 2000. © 2000 Wiley‐Liss, Inc.

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Recently, we developed a series of cytotoxic peptide conjugates containing 14-O-glutaryl esters of doxorubicin (DOX) or 2-pyrrolino-DOX (AN-201). Serum carboxylesterase enzymes (CE) can partially hydrolyze these conjugates in the circulation, releasing the cytotoxic radical, before the targeting is complete. CE activity in serum of nude mice is about 10 times higher than in human serum.