We have recently demonstrated that overexpression of
dihydrodiol dehydrogenase (DDH) in human ovarian
carcinoma cells (2008/C13*) is associated with
cisplatin and
carboplatin resistance. Furthermore, we have also elucidated that transfection of parental human ovarian
carcinoma cells with a full-length DDH1
cDNA leads to induction of resistance to the
platinum drugs. The development of
cisplatin resistance in the transfected cells is associated with an increase in DDH
enzyme activity. Previous studies have identified several different mechanisms for development of
cisplatin resistance, including altered DNA repair capacity, increased GSH-based detoxification, and increased
metallothionein content. However, none of these mechanisms has been found to be universally associated with the development of
cisplatin resistance in
tumor cells from different tissue sources. The present study was undertaken to assess whether overexpression of DDH1 or DDH2 (in human ovarian, cervical, lung and
germ-cell tumor cell lines) could specifically induce resistance to the
platinum drugs in these cell lines. We demonstrated a ubiquitous association of increased expression of DDH1 or DDH2 (as judged by increased
enzyme activity in transfected clones) with development of resistance to
cisplatin and
carboplatin. Moreover, we also found a lack of cross-resistance to anticancer drugs that have a different mode of action including
paclitaxel,
vincristine,
doxorubicin hydrochloride, and
melphalan. Although at present it is not clear how DDH is involved in
platinum drug resistance, the identification of this gene as a causal factor in a series of cell lines derived from different
tumors with different intracellular compositions indicates the importance of deciphering this hitherto undefined pathway which can produce resistance to
platinum drugs.