2005 Abstracts: Antisense Therapy Specific To Mutated K-Ras Gene in Hamster Experimental Pancreatic Cancer Model In Vitro and In Vivo:Is There Some Promise in This Approach?
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Antisense Therapy Specific To Mutated K-Ras Gene in Hamster Experimental Pancreatic Cancer Model In Vitro and In Vivo:Is There Some Promise in This Approach?
Cintia Yoko Morioka, Marcel C. Machado, University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil; Seiji Saito, 3rd Depart of Internal Medicine, Toyama, Toyama, Japan; Gabriela I. Yamago, Okayama University Medical School, Okayama, Okayama, Japan; Andre S. Matheus, Jose E. Cunha, Jose Jukemura, University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil; Akiharu Watanabe, Toyama Medical and Pharmaceutical University, Toyama, Toyama, Japan
Background: Pancreas cancer prognosis is still reserved constituting a medical challenge. About >90% of this type of cancer carries K-ras point mutation, which may play an important role in tumoral progression. Antisense oligonucleotides (ASO) targeting this gene may be a therapeutic choice.
Aims: To elucidate the effectiveness of this gene therapy in hamster experimental pancreatic cancer model. Materials and Methods: HaP-T1, a cell culture derived from nitrosamine-induced hamster pancreatic cancer was used. MTT, MTT-Agarose, Western blotting, and in vitro chemoinvasion assay were performed using ASO specific to K-ras gene. In exponential phase of growth, a tissue derived from subcutaneously implanted cancer cells was implanted into the pancreas. Animals were divided in 3 groups: 1. Positive control (PC), 2. Sense treated hamsters (STH), and 3. Antisense treated hamsters (ATH). Oligonucleotides were administered for 2 weeks. Follow up was done by evaluation of the tumor growth by palpation, ggeneral stateh, weight, and side effects. Five animals of each group were sacrificed at Days 10, 17, 24, 31, 38, to study the local response and metastatic sites. Five animals of each group were left to study the survival time. Necropsy was performed and specimens were studied histopathologically. Results: ASO inhibited the tumoral growth by suppression of K-ras p21 protein synthesis. It could also inhibit the invasiveness. All tumors were palpable. Positive controls, STH, and ATH survived in average 72.7, 73.8, and 79.6 days, respectively. Side effects were observed in both oligonucleotide-injected groups. Tumor sizes were in average smaller in ATH throughout the study. Spontaneous lymph node metastases were found from 31 days in ATH group, while PC and STH groups showed metastases and direct invasion to adjacent organs from 17 days. After death, metastatic sites were similar in the 3 groups. Liver metastasis has an incidence higher in PC. Moreover, only PC group showed ascites. Conclusions: Antisense oligonucleotides inhibited tumor growth and invasiveness, improved liver metastatic rate and ascites. Therefore, it may be a good approach in the management of pancreatic cancer. Moreover, it may contribute as neoadjuvant and/or adjuvant therapy.
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