Cisplatin resistance

Dimeric complexes like [Cl(NH3)Pt H2N(CH2)4NH2 Pt(NH3)Cl]Cl2 are also being investigated as they bind to DNA in a different way to that involved in cisplatin binding and are active in cisplatin-resistant human tumour cells. They are more potent than cisplatin in lung cancer models in vivo and are likely to go on clinical trials in the near future [204],... 

Kawakami, M., Kagotani, K., Okumura, K., Akiyama, S., Kuwano, M., A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation, Cancer Res. 1996, 56, 4124-4129. 

Uchiumi T, Hinoshita E, Haga S, Nakamura T, Tanaka T, Toh S et al. Isolation of a novel human canalicular multispecific organic anion transporter, cMOAT2/MRP3, and its expression in cisplatin-resistant cancer cells with decreased ATP-dependent drug transport. Biochem Biophys Res Commun 1998 252(1)703-110. 

In phase I clinical trials 47 patients, all of whom had previously failed standard treatments for solid tumors, received the drug in the UK, Italy, and Switzerland on three different schedules.123,124 Dose-limiting toxicities have been defined as bone marrow depression and diarrhea. The latter is treatable with loperamide. Signs of biological activity were seen. Notably one patient with metastatic pancreatic cancer showed a partial response (for 4 months) and two further patients, one with metastatic melanoma and one with bronchoalveolar carcinoma, also showed partial responses. In a phase I trial in combination with 5-FU, a partial response in breast cancer was observed.125 Furthermore, a reduction in tumor marker levels was observed in two patients, one with ovarian cancer, and one with colon cancer. Phase II studies have shown partial responses in cisplatin-resistant ovarian and nonsmall-cell lung cancer.126,127 The indications are that the profile of clinical activity is different and complementary to the mononuclear platinum agents. 

Fig. 7. Effect of light on the IC50 values for the inhibition of cell growth of various cancer cell lines by platinum(IV) diazido complexes, (a) toxicity of the cis-complexes 4 and 5 on human bladder cancer cell lines (5637-CDDP, cisplatin-resistant cell line) (b) comparison of cytotoxicities of the cis- and rarcs-isomers 4 and 6 in the dark and upon irradiation cisplatin is included for comparison. Data from Ref. (30).

SH-SY5Y neuroblastoma, cisplatin-sensitive A2780 and cispla-tin-resistant A2780cis human ovarian cancer cells was observed, but upon irradiation 7 strongly reduced the viability of the cancer cells (Fig. 8). In the A2780 cell line, the complex was 80x more toxic than cisplatin under identical conditions, and ca. 15 x more effective against the cisplatin-resistant A2780cis cell line (33). The trans diazido-Pt(IV) complex therefore has remarkable cytotoxic properties. 

The fourth criteria, that of oral administration, is being developed and evaluated for ZD0473 as just mentioned. Another candidate in this field, JM216, cis, trans, cw-[dichlorodiacetatoammine(cyclohexylamine)platinum(IV)] (see Figure 7.6D), is an orally active platinum(IV) drug being evaluated in clinical trials. This platinum (IV) complex has demonstrated activity in cisplatin-resistant tumors and exhibits less nephrotoxicity and neurotoxicity than does cisDDP. 

Intracellular thiolate ligands such as glutathione (GSH, the tripeptide y-L-Glu-L-Cys-Gly) are believed to inactivate cisplatin because the reactions with cisplatin tend to be irreversible (35). Elevated levels of GSH have been observed in cisplatin-resistant cells. Recently, it has been shown that an MRP gene, which encodes a human ATP-dependent glutathione S-conjugate export pump (GS-X pump), is expressed at higher levels in cisplatin-resistant (HL-60/R-CP) cells than in sensitive cells (36). The GS-X pump may contribute to the excretion of Pt-GS complexes from cells (37). 

Although the second generation of platinum drugs is less toxic than cisplatin, many appear to be cross-resistant with cisplatin. Requirements which are influencing the search for new generations of active complexes include (1) lower toxicity to normal cells than cisplatin, (2) activity against tumors with acquired cisplatin resistance, (3) activity against a wider spectrum of types of cancer, and (4) oral activity. 

The sterically hindered complex 9 (AMD 473, ZD0473) is active (injection and oral) against an acquired cisplatin-resistant subline of a... 

Ma J, Maliepaard M, Kolker HJ, Verweij J, Schellens JHM (1998a) Abrogated energy-dependent uptake of cisplatin in a cisplatin-resistant subline of the human ovarian cancer cell line IGROV-1. Cancer Chemother Pharmacol 41 186-192... 

Scaglione-Sewell B, Abraham C, Bissonnette M, Skarosi SF, Hart J, Davidson NO, Wali RK, Davis BH, Sitrin M, Brasitus TA (1998) Decreased FKC alpha expression increases cellular proliferation, decreases differentiation, and enhances the transformed phenotype of CaCo-2 cells. Cancer Res 58 1074-1081 Scala S, Dickstein B, Regis J, Szallasi Z, Blumberg PM, Bates SE (1995) Bryostatin 1 affects P-glycoprotein phosphorylation but not function in multidrug-resistant human breast cancer cells. Clinical Cancer Res 1 15851-1587 Scanlon, KJ, Kashani-Sabet M, Tone T, Funato T (1991) Cisplatin resistance in human acancers. Pharmac Ther 52 385-406... 

Lanzi C, Perego P, Supino R, et al. Decreased drug accumulation and increased tolerance to DNA damage in tumor cells with a low level of cisplatin resistance. Biochem Pharmacol 1998 55 1247-1254. 

Fujii R, Mutoh M, Sumizawa T, Chen Z, Yoshimura A, Akiyama S. Adenosine triphosphate-depen-dent transport of leukotriene C4 by membrane vesicles prepared from cisplatin-resistant human epidermoid carcinoma tumor cells. J Natl Cancer Inst 1994 86 1781-1784. 

Brown R. Cisplatin resistance in ovarian cancer. In (Kelland LR, Farrell N, eds) Platinum-Based Drugs in Cancer Therapy 2000 Humana Press Inc. Totowa, NJ pp. 115-128. 

The same premises of customization can be applied to early NSCLC. Various clini-eal observations indieate that when these defense NER genes are overexpressed in re-seeted NSCLCs, they reflect a lower risk of relapse and increased cisplatin resistance. Several layers of evidence show that BRCAl can be the most important predictive marker for eustomizing chemotherapy. In addition, the clinical value of several mitotic checkpoint genes that are dysfunctional in NSCLC and regulated by BRCAl should also be investigated. 

High tumor tissue levels of ERCCl mRNA in ovarian and gastric cancer patients have been associated with cisplatin resistance (24,25). Similarly, inhibition of ERCCl expression has been significantly associated with reduced HCR of cisplatin-treated cells... 

The in vitro antitumor activity of curcumin in HPV-associated cells has been established [Roy et al., 2002]. Curcumin modulates the in vitro expression and function of Pgp in multidrug-resistant human KB-V1 cells [Anand et al., 2008 Chearwae et al., 2004] and sensitizes cisplatin-resistant SiHa cells to cisplatin-induced apoptosis [Venkatraman et al., 2005], indicating its ability to reverse MDR in cervical cancer cells. The effect of curcumin in HPV-associated cells was found to involve the down-regulation of viral oncogenes, NF-kB and AP-1 [Anand et al., 2008 Divya and Pillai, 2006],... 

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