Identification of a candidate gene associated with paclitaxel-resistance and application to a gene therapy in ovarian cancer.

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We established an in vivo paclitaxel-resistant cell line from the parental human ovarian cancer cell lines by repeated paclitaxel administration into tumor-bearing mice. We performed cDNA microarrays between in vivo established paclitaxel-resistant cell line and in vivo established control group to identify the target genes associated with paclitaxel-resistancy. Total RNAs were extracted (1) from in vivo established paclitaxel-resistant cell lines and control group, and (2) from tumor blocks (OM1TX6T and OM1P6T)which were made by subcutaneous transplantion of paclitaxel-resistant cells or control cells.cDNA were purified and cancer-related gene manifestation profiles which were specifically increased or decreased between two groups were identified. Genes which we used for analysis (1) were 9,063, and the number of the genes which expressed in a resistant cell lines more than double of control cell lines. In addition, genes which we used for analysis (2) were 8,660,and similarly the number of the genes which expressed OM1TX6T more than double of OM1P6T was 298. Now we really push forward extraction of genes related to paclitaxel-resistance from these genes.On the other hand, overexpression of class III B-tubulin was attracted attention as mechanism of taxane-resistance. We evaluated protein expression level of class I, II, II, IV (IVa+IVb) isotypes of B-tubulin in an ovarian cancer specimens by immunohistochemical stainig, and examined the association with responce to taxane-containing chemotherapy. As a result, in the goup which had chemotherapy with taxane, high expression of class III isotypes of B-tubulin tend to correlate with short prograssion free survival (p=0.081), while this tendency was not found in the group which had chemotherapy without taxane.