Three-Dimensional, but not Two-Dimensional, Culture Results in Tumor Growth Enhancement after Exposure to Anticancer Drugs

Previously, we have adapted a recently developed three-dimensionalchemosensitivity test, the collagen gel droplet embedded culture drug sensitivity test(CD-DST), for evaluation of chemosensitivity of 12 anticancer drugs against colorectaladenocarcinoma, and surprisingly, it was found that tumor growth enhancement wasoccasionally observed even after exposure to anticancer drugs. In this study, theCD-DST was applied for human cervical carcinoma cell line HeLa-Ohio (HeLa) cellsand its MDR1/P-glycoprotein-overexpressing subline, Hvr100-6 cells, and 12 anticancerdrugs were assessed in terms of chemosensitivity and deterioration of tumor, and theresults were compared with those by two-dimensional WST-1 assay. Growthenhancement was observed in Hvr100-6 cells, not in HeLa cells, for mitomycin C withthe ratio of total volume of colonies in the treated group to that in the untreated group(T/C%) of 135.0%, doxorubicin with T/C% of 162.5% and cyclophosphamide withT/C% of 122.0%, and this was not observed in WST-1 assay. Multidrug resistancewas detected both for CD-DST and WST-1 assay. The values of T/C% in CD-DSTwere comparable with or higher than those of the survival fraction (%) in WST-1 assay,and modification of WST-1 assay procedure gave similar results, suggesting a higherresistance in three-dimensional than in two-dimensional culture. Furtherinvestigations should be addressed to the association of MDR1/P-glycoprotein withtumor growth enhancement

Reversal Effects of Ca2+ Antagonists on Multidrug Resistance via Down-regulation of MDR1 mRNA

In previous reports, the effects of 12 Ca2+ antagonists on a multidrug resistanttransporter, P-glycoprotein/MDR1, were evaluated in terms of those onMDR1-mediated transport of [3H]digoxin and the sensitivity of vinblastine sulfate orpaclitaxel, and they were able to be classified into 4 subgroups based on their actions,as those with transport inhibition and sensitivity recovery, those with or withouttransport inhibition but marginal sensitivity recovery, and those without both. Inthis study, our previous findings were confirmed by the resistance against doxorubicinhydrochloride and daunorubicin hydrochloride, and by the recovery of [3H] vinblastinesulfate accumulation. Furthermore, it was found that the effects of 12 Ca2+antagonists on the sensitivity recovery were also explained by the down-regulation ofMDR1 mRNA, suggesting a novel mechanism to reverse the MDR1-mediatedmultidrug resistance