Radiation will overcome acquired chemo-resistance with cisplatin in gastric cancer cell.

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Background: Recently, combination chemotherapy with cisplatin (CDDP) becomes one of effective treatment against gastric cancer, clinically. CDDP will be one of key drugs for combination with newly developed anticancer drug like taxanes. We previously reported that CDDP antitumor effect will be enhanced by taxanes through suppression of dynamic increase of MRP-1 expression responding to CDDP (Cancer Sci. 95, 679-84, 2004), Thus, several reports mentioned that chemosensitivity to an anticancer drug in a kind of cancer cell will be enhanced by another drug after molecular modification in some mechanism inside the cell. On the other hand, clinically, acquired chemo-resistant cell against an anticancer drug after therapy will be a critical problem to be solved, urgently. In the present study, we attempt to establish a resistant gastric cancer cell to CDDP, and to overcome the resistant mechanism by radiation, which will be one of potent therapies for gastric cancer. Methods:We established CDDP-resistant gastric cancer cell lines using TMK-1 and MKN-74 with long-term exposure (several months) with low concentration of CDDP (TMK-1/D and MKN-74/D). Evaluation of each cell resistance was performed with MTT method. IC50s were calculated with each concentration-survival curve. Results:(1)The IC50s of CDDP were as follows: TMK-1 2.14±0.46μg/ml, TMK-1/D 7.20±1.66μg/ml, MKN-74 6.69±3.19μg/ml, and MKN-74/D 40.49±10.02μg/ml, as the IC50 value of TMK-1/D to TMK-1 was 3.36 fold, and the IC50 value of MKN-74/D to MKN-74 was 6.05 fold. (2)Interestingly, radiation sensitivity (in 8 Gy alone without chemotherapy) will be decreasing in each resistant cell, as each survival ratio of TMK-1 and TMK-1/D with 8Gy radiation is 44.6%, 55.5%,respectively, and that of MKN-74 and MKN-74/D is 33.5 and 59.6%, respectively. And radiation dose-dependency was also confirmed in all cell lines. (3)The IC50 of CDDP in each cell lines, which was calculated with different schedule from experiment (1), was described as follow: TMK-1; 0.186μg/ml, TMK-1/D; 0.678μg/ml, TMK-1/D with radiation followed by CDDP; 0.393μg/ml, TMK-1/D with CDDP followed by radiation; 0.245μg/ml, MKN-74; 0.302μg/ml , MKN-74/D 0.9453μg/ml, MKN-74/D with radiation followed by CDDP; 0.166μg/ml, and MKN74/D with CDDP followed by radiation; 0.0994μg/ml. Conclusion: Radiation might have potent possibilities to re-control and overcome acquired resistance to CDDP after exposure with CDDP in gastric cancer cell lines. And, radiation may be modifying some acquired resistant mechanism to CDDP in gastric cancer cells.