RESUMO
UNLABELLED: K-ras point mutation at codon 12 has a relationship greater than 90% with pancreatic cancer. Cancer therapy should also include the treatment of metastatic disease because it is known that the properties of metastatic cells may vary considerably from those of the primary tumor. AIM: To clarify if the same drugs, which can inhibit the tumor growth in the parental cell line, can inhibit the pancreatic metastatic and remetastatic cell lines at the same concentrations and to compare the inhibition with antisense oligonucleotides mismatched to K-ras gene, in Syrian golden hamsters. MATERIALS AND METHODS: HaP-T1, a BHP-induced hamster pancreatic cancer cell line, MS-PaS-1 (a metastatic cell line established from "return trip" metastases from the liver to the pancreas) and MS-PaS-2 named as a "remetastatic cell line", i.e., metastases from MS-PaS-1 were used. MTT and MTT-agarose assays were performed, using 5-Fluorouracil (5-FU), Mitomycin C (MMC) and antisense oligonucleotide specific to K-ras oncogene. RESULTS: The inhibitory concentration (IC50) of 5-FU, which inhibited HaP-T1, had to be increased by 50-fold to inhibit MS-PaS-1 and 100-fold to inhibit MS-PaS-2. MMC had to be increased by 10-fold to inhibit MS-PaS-1 and 50-fold to inhibit MS-PaS-2. However, IC50 was the same when antisense oligonucleotide was tried in these 3 cell lines. CONCLUSION: Antisense oligonucleotide-targeted K-ras gene may be a good choice for therapy because it could inhibit the growth in metastatic and remetastatic cells as well as in primary tumor cells.
Assuntos
Genes ras , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Transplante de Células , Cricetinae , DNA de Neoplasias/genética , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/farmacologia , Neoplasias Hepáticas Experimentais/patologia , Masculino , Mesocricetus , Mitomicina/farmacologia , Mutação , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Transplante de Neoplasias , Oligonucleotídeos Antissenso/farmacologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/secundárioRESUMO
The major cause of death in patients with pancreatic cancer is metastatic disease. In fact, at the time of diagnosis, patients usually have locally advanced or metastatic disease involving lymph nodes, liver, lungs or peritoneum. Therefore, for a better understanding of the tumoral behavior to design prevention or treatment strategies, in vivo models are important. We report here the results of the metastatic behavior of parental and metastatic cell lines in a hamster pancreatic cancer model when implanted orthotopically (OIH,OIM) or into the liver (LIH,LIM). Metastatic sites and survival were studied. Survival ranged from 72 to 105 days. The OIH group showed spontaneous metastases to lymph nodes. The second target organ was the lung. Liver metastases appeared earlier in the OIM group than OIH. LIH showed only metastases to the pancreas while the LIM group showed metastases to pancreas, vas deferens and testis. This study suggests that the metastatic behavior of parental and metastatic cell lines is different. Thus, this should be considered in the planning of clinical or surgical treatment against pancreatic cancer.
