Antisense therapy specific to mutated K-ras gene in hamster pancreatic cancer model. Can it inhibit the growth of 5-FU and MMC-resistant metastatic and remetastatic cell lines?
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.


OBJECTIVE
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.


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.


CONCLUSIONS
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.
Morioka
Cíntia Yoko
CY
Department of Surgery, University of São Paulo, Brazil. morioka@gvmail.br
Saito
Seiji
S
Machado
Marcel Cerqueira Cesar
MC
Ohzawa
Kouji
K
Kubrusly
Márcia Saldanha
MS
Cunha
José Eduardo Monteiro
JE
Watanabe
Akiharu
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D017690:Cell Transplantation; D006224:Cricetinae; D004273:DNA, Neoplasm / Q000235:genetics; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000494:pharmacology; D011905:Genes, ras; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D016685:Mitomycin / Q000494:pharmacology; D009154:Mutation; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D016376:Oligonucleotides, Antisense; D016685:Mitomycin; D005472:Fluorouracil