DIFFERENTIAL-EFFECTS OF ALL-TRANS-RETINOIC ACID, DOCOSAHEXAENOIC ACID, AND HEXADECYLPHOSPHOCHOLINE ON CISPLATIN-INDUCED CYTOTOXICITY AND APOPTOSIS IN A CISPLANTIN-SENSITIVE AND RESISTANT HUMAN EMBRYONAL CARCINOMA CELL

Apart from modulation of tumor-cell drug sensitivity, induction of dif ferentiation might be an alternative in the treatment of tumors resist ant to cytotoxic drugs. In this report the capacity to induce differen tiation and to modulate the cis-diamminedichloroplatinum(II) (CDDP) se nsitivity of all-trans-retinoic acid (RA), docosahexaenoic acid (DCHA) , and hexadecylphosphocholine (HePC) is examined in human germ-cell tu mor cell lines. In the embryonal carcinoma cell line Tera-2 and its 3. 7-fold CDDP-resistant subline Tera2-CP, we evaluated the effects of 96 h of pretreatment with RA (0.1 mu M), DCHA (23 mu M), and HePC (25 mu M) on differenctiation induction and on CDDP-induced cytotoxicity, DN A platination (4-h incubation), and apoptosis (continuous incubation). Without drug treatment. Tera2-CP showed less apoptosis than Tera-2. P retreatment with RA decreased the cytotoxicity and apoptosis induced b y CDDP without resulting in decreased DNA platination and increased di fferentiation in both cell lines. DCHA enhanced CDDP-induced cytotoxic ity and apoptosis and did not affect the embryonal character of either cell line. HePC did not affect CDDP cytotoxicity or differentiation i n either cell lines. Effects of the modulators on differentiation and on CDDP-induced cytotoxicity, DNA platination, and apoptosis did not d iffer between Tera-2 and Tera2-CP. RA can be applied for differentiati on induction in CDDP-resistant germ-cell tumor models. However, in thi s model, RA reduced the apoptotic susceptibility. DCHA potentiated CDD P cytotoxicity in vitro; its in vivo modulatory capacity in germ-cell tumor cells deserves further study.