Abstract 3548: Selective targeting of pancreatic tumors lacking methylthioadenosine phosphorylase (MTAP)

Abstract

Abstract The pancreatic cancer cell line, Mia PACA, lacks MTAP, and as a result is unable to salvage adenine and methionine, products of methylthioadenosine (MTA) metabolism by MTAP, and is more sensitive to de novo purine synthesis inhibitors (thiopurines, methotrexate, azaserine and L-alanosine). In addition, MTAP deficiency creates a condition where normal, but not tumor tissues, can be protected from 5-fluorouracil (5-FU) toxicity by MTA. In normal tissue, MTA is converted to adenine, consuming 5-phosphoribose-1-pyrophosphate (PRPP) and competitively inhibiting phosphoribosylation of 5-FU (and subsequent cellular retention and inhibition of thymidylate synthase and incorporation into RNA). In MTAP deficient tumors, MTA can not generate adenine; the relative lack of adenine, and abundance of PRPP favors phosphoribosylation of 5-FU to nucleotides. The MTAP gene is linked to the tumor suppressor p16INK4 locus on chromosome 9p21. This locus is frequently deleted in human cancer. As a result, relative or complete MTAP deficiency is common in several human cancers, including pancreatic cancer (33%). We have transfected the Mia PACA cell line with MTAP cDNA and generated three sublines that express MTAP. The parenteral cell line lacking MTAP expression is more sensitive to 5-FU (4 h treatment), and toxicity is not ameliorated by pretreatment with MTA. In contrast, the three sublines expressing MTAP are a log less sensitive to 5FU, when pretreated with MTA. As pancreatic cancer is known to be somewhat responsive to treatment with 5-FU, but doses are limited by toxicity, the protection of the host from toxicity by MTA pretreatment may allow higher doses of 5-FU to be safely given and allow gemcitabine, another antimetabolite used to treat patients with pancreatic cancer, to be added in full doses. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3548. doi:10.1158/1538-7445.AM2011-3548