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.
Highlights
Pancreatic carcinoma is the 9th most common human cancer in the Western world, including the USA, but it is the fourth leading cause of cancer death in both males and females. [1] Its incidence has increased in the white www.impactjournals.com/oncotargetOncotarget 2013; 4: 751-760 population by about 1% per year between 1999 through 2008. [2] Ductal carcinomas of the pancreas are very aggressive tumors, and because of the concealed location of the gland, they are mostly detected in late stages of development when surgical removal is not useful
One possible way to increase the efficacy of therapy is to target drugs to specific molecular components in cancer cells, such as growth factors and their receptors, a or proliferation-promoting kinases etc. [13,14,15,16] Specific receptors for hypothalamic peptide hormones, including LH-RH, somatostatin and bombesin have been detected in various cancers, and these receptors may serve as targets for the peptide ligand linked to a cytotoxic agent. [13, 15, 17,18,19,20,21] we have developed new classes of targeted antitumor agents by linking doxorubicin (DOX), or its derivative, 2-pyrrolino-DOX (AN-201), to LHRH, somatostatin and bombesin
Based on information that receptors for somatostatin and bombesin are expressed in pancreatic cancers we tested the effects of cytotoxic analogs of somatostatin (AN-238) and bombesin (AN-215) on human pancreatic cancer lines xenografted into nude mice
Summary
Pancreatic carcinoma is the 9th most common human cancer in the Western world, including the USA, but it is the fourth leading cause of cancer death in both males and females. [1] Its incidence has increased in the white www.impactjournals.com/oncotargetOncotarget 2013; 4: 751-760 population by about 1% per year between 1999 through 2008. [2] Ductal carcinomas of the pancreas are very aggressive tumors, and because of the concealed location of the gland, they are mostly detected in late stages of development when surgical removal is not useful. [13,14,15,16] Specific receptors for hypothalamic peptide hormones, including LH-RH, somatostatin and bombesin have been detected in various cancers, and these receptors may serve as targets for the peptide ligand linked to a cytotoxic agent. [13, 15, 17,18,19,20,21] we have developed new classes of targeted antitumor agents by linking doxorubicin (DOX), or its derivative, 2-pyrrolino-DOX (AN-201), to LHRH, somatostatin and bombesin Since these cytotoxic compounds are targeted to receptors for these specific hormones on tumor cells, the concentration of the toxic agent in tumor tissue is increased and normal cells are spared from exposure to toxicity. AN-238 and AN-215 significantly inhibited growth of SW-1990, Panc-1, CFPAC-1, Capan-1 and Capan-2 tumors each of which expresses various subtypes of somatostatin receptors and bombesin receptors. [22, 23] LH-RH and its receptor are not confined to the hypothalamic-pituitary axis. [24] In the periphery, the LH-RH system coordinates gonadal functions and serves as a growth factor of benign conditions [25,26,27,28] and various malignancies. [29, 30] Following our first demonstration of LH-RH receptors b c d
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