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Tumors are composed of abnormally transformed cell types and tissues that differ from normal tissues in their genetic and epigenetic makeup, metabolism, and immunology. Molecular compounds that modulate the immune response against neoplasms offer promising new strategies to combat cancer. Inhibitors targeting the indoleamine-2,3-dioxygenase 1 enzyme (IDO1) represent one of the most potent therapeutic opportunities to inhibit tumor growth. Herein, we assess the biochemical role of IDO1 in tumor metabolism and immune surveillance, and review current diagnostic and therapeutic approaches that are intended to increase the effectiveness of immunotherapies against highly aggressive and difficult-to-treat IDO-expressing cancers.

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Doxorubicin (DOX) and its daunosaminemodified derivative, 2-pyrrolino-DOX, which is 500-1000 times more active than DOX, were incorporated into agonistic and antagonistic analogs of luteinizing hormone-releasing hormone (LH-RH). The conjugation of DOX with LH-RH analogs was performed by using N-(9-fluorenylmethoxycarbonyl)-DOX-14-0-hemiglutarate, a dicarboxylic acid ester derivative of DOX. Coupling this derivative covalently to the[where Nal(2) = 3-(2-naphthyl)alanine, Pal(3) = 3-(3-pyridyl)alanine, and Phe(4CI) = 4-chlorophenylalanine] was followed by the removal of the 9-fluorenylmethoxycarbonyl protective group to yield cytotoxic derivatives of LH-RH analogs containing DOX. From these DOX containing LH-RH hybrids, intensely potent analogs with daunosamine-modified derivatives of DOX can be readily formed. Thus, cytotoxic LH-RH agonist containing DOX (AN-152) can be converted in a 66% yield by a reaction with a 30-fold excess of 4-iodobutyraldehyde in N,Ndimethylformamide into a derivative having 2-pyrrolino-DOX (AN-207). Hybrid molecules AN-152 and AN-207 fully preserve the cytotoxic activity of their radicals, DOX or 2-pyrrolino-DOX, respectively, in vitro, and also retain the high binding affinity of the peptide hormone portion of the conjugates to rat pituitary receptors for LH-RH. These highly potent cytotoxic analogs of LH-RH were designed as targeted anti-cancer agents for the treatment of various tumors that possess receptors for the carrier peptide. Initial in vivo studies show that the hybrid molecules are much less toxic than the respective cytotoxic radicals incorporated and significantly more active in inhibiting tumor growth.

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...