Enhancement of antitumour activity of cisplatin by N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine. HCl in human ovarian cancer cells with intrinsic or acquired resistance to cisplatin.

Abstract

This study was designed to the elucidate sensitising effects of the intracellular histamine antagonist, N,N-diethyl-2[4-(phenylmethyl)phenoxy] ethanamine HCl (DPPE) on the antitumour activity of cis-diamminedichloroplatinum (II) (CDDP) using human ovarian cancer cell lines with different sensitivities to CDDP (KF, sensitive) KFra (acquired CDDP resistant derived from KF), and KK and MH, intrinsically CDDP resistant. The KF cells were most sensitive to CDDP among cell lines used in this study and followed by MH, KK and KFra showing approximately 3.5, 4.0 and 9.1-fold IC50 values to KF, respectively. The acquired CDDP resistant KFra cells were approximately 6.1-fold more sensitive to DPPE than the parent KF cells, while MH and KK cells were more than 10-fold more resistant to DPPE than the KF cells. With regard to the inhibition of human ovarian cancer cell proliferation, phenyltoloxamine and L-histidinol were 5-2500-fold less cytotoxic than DPPE. Analysis of flow cytometry (FCM) revealed that with concentrations based on the IC50 to KF and KFra cells, DPPE resulted in G2-M accumulation in the KF (but not KFra) cells in a time-dependent manner during the course of 48 h incubation time. In addition, from a median effect analysis, DPPE seemed to have additive and somewhat synergistic effects on the antitumour activity of CDDP in KK and MH cells with intrinsic CDDP resistance, while minor antagonism in KFra cells with acquired CDDP resistance was observed. Although DPPE alone did not significantly inhibit the tumour growth of nude mice bearing KF cells, combinations of DPPE with CDDP resulted in improved survival compared with treatment with only CDDP. Adverse side-effects, as confirmed by monitoring haematocrit and the body weight were not observed during the experimental period. These results suggest that DPPE may be of clinical use for the treatment of intrinsically refractory ovarian carcinoma when combined with CDDP.