Powerful Inhibition of Experimental Human Pancreatic Cancers by Receptor Targeted Cytotoxic LH-RH analog AEZS-108

Abstract

Pancreatic carcinoma is one of the cancers with the worse prognosis, thus any therapeutic improvement is imperative. Cytotoxic LH-RH analog, AN-152 (proprietary designation, AEZS-108), consisting of doxorubicin (DOX) conjugated to D-Lys6LH-RH, is now in clinical trials for targeted therapy of several sex hormone-dependent tumors that express LH-RH receptors. We investigated LH-RH receptors in human pancreatic carcinoma and the effects of AN-152 (AEZS-108) on experimental pancreatic cancers. We determined LH-RH receptor presence in human pancreatic cancer samples by immunohistochemistry and, in three human pancreatic cancer lines (SW-1990, Panc-1 and CFPAC-1), by binding assays and Western blotting. The effects of the cytotoxic LH-RH analog were investigated on growth of these same cancer lines xenografted into nude mice. We also analyzed differences between the antitumor effects of the cytotoxic analog and its cytotoxic radical alone, doxorubicin (DOX), on the expression of cancer-related genes by PCR arrays. LH-RH receptors were expressed in two randomly selected surgically removed human pancreatic cancer samples and in all three cancer lines. Cytotoxic LH-RH analogs powerfully inhibited growth of all three tumor lines in nude mice; AN-152 was significantly stronger than DOX on Panc-1 and CFPAC-1 cancers. PCR array showed that cytotoxic LH-RH analog AN-152 affected the expression of genes associated with cellular migration, invasion, metastasis and angiogenesis more favorably than DOX, however the changes in gene expression varied considerably among the three cancer lines. Cytotoxic LH-RH analog, AEZS-108, may be a useful agent for the treatment of LH-RH receptor positive advanced pancreatic carcinoma.

Potentiating effects of GHRH analogs on the response to chemotherapy

“…Among the affected pathways are the PI3K/AKT and inflammatory cytokine pathways that regulate EMT. 18,25,37 This reduction as described above in the expression of the multidrug resistance (MDRI) gene, the drug resistance regulator, NANOG, and the suppression of efflux pump function produced by GHRH antagonists in doxorubicintreated HCC1806 and MX-1 breast cancers was similar to those obtained in many cancers employing other therapies targeted to peptide receptors of tumors, using, for example, cytotoxic analogs of luteinizing hormone-releasing hormone (LHRH), AN-152 or AN-207, [38][39][40][41][42] or other targeted cytotoxic analogs including AN-162 and AN-238 [43][44][45][46] which are based on somatostatin. 47,48 In both circumstances of therapy with GHRH antagonists or other targeted analogs these findings clearly demonstrate a more efficacious chemotherapeutic result by the mechanism of disabling of the efflux pumps and the reduction in resulting resistance to chemotherapy.…”

Oxime bond-linked daunorubicin-GnRH-III bioconjugates exert antitumor activity in castration-resistant prostate cancer cells via the type I GnRH receptor

“…These side effects were mainly attributed to the cleavage of the ester bond in circulation, leading to the release of free Dox and [D-6 Lys(glutarate)]-GnRH-I; the half-life of AESZ-108 was estimated to be about 2 h. AEZS-108 is at present in phase III studies in advanced endometrial cancer positive for GnRH-R (30). Recently, this compound has been shown to exert a cytotoxic effect on human urinary bladder, glioblastoma and pancreatic cancer cells, in vitro and in vivo (32)(33)(34).…”

Effects of Garlic Oil on Pancreatic Cancer Cells

“…Pancreatic cancer patients have been suffering from limited treatment options due to late diagnosis, poor drug tolerance, and multi-drug resistance to almost all the current drug treatments, which was considered to be the most serious problem at present (Guo et al, 2013;Won et al, 2013;Szepeshazi et al, 2013). Therefore, it is significant for us to seek an alternative therapeutic medicines which can effectively prevent the disease and even eradicate the progression and metastasis of pancreatic cancer.…”