Cisplatin is effective against a wide range of solid organ cancers including the following; testicular, ovarian, breast, cervical, and head and neck. Its site of action is thought to be the guanine residues in the DNA chain forming inter and intrastrand cross-links. Unfortunately, cancer cells which are initially often responsive, develop resistance, limiting its effectiveness.
There have been many studies attempting to find specific markers for resistance to cisplatin, including genes in the AKT, ROS, 14-3-3 zeta, ER stress and cell cycle pathways. However, when a stable resistant ovarian cancer cell line was analyzed with cDNA microarrays followed by cDNA transfection of the candidate genes, an enzyme dihydrodiol dehydrogenase, (which has been previously implicated in the metabolic reduction and activation/inactivation of several xenobiotics) was found to produce cisplatin resistance. We showed that transfection or knockout of this enzyme from a whole series of tumor cell lines, including those derived from lung, cervical, testicular, ovarian primary tumors; resulted in significantly increased (transfection) or decreased (knockout) resistance to cisplatin.
Recently, we have found that this enzyme is implicated in cisplatin resistance in lung adenocarcinomas, but not mesotheliomas nor small cell carcinomas. In addition, another enzyme which has previously been implicated in platinum resistance, (glutathione transferase pi) was found to be present in cell lines which do not contain dihydrodiol dehydrogenase (e.g. hematologic and lung mesothelioma cell lines). Knockdown of this enzyme resulted in sensitization of a whole series of lymphoma cell lines to both cisplatin and oxaliplatin-drugs that have been used successfully in previously-treated patients with refractory lymphomas. The ultimate aim of this work is to determine whether inhibitors to these two enzymes will sensititize resistant cells to platinum based chemotherapy.