Cisplatin-sensitive

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. 

Basu A, Cline JS (1995) Oncogenic transformation alters cisplatin induced apoptosis in rat embryo fibroblasts. Int J Cancer 63 597-603 Basu A, Weixel KM (1995) Comparison of protein kinase C activity and isoform expression in cisplatin-sensitive and -resistant ovarian carcinoma cells. Int J Cancer 62 457-460... 

Johnson SW, Shen DW, Pastan I, Gottesman MM, Hamilton TC. Cross-resistance, cisplatin accumulation and platinum-DNA adduct formation and removal in cisplatin-sensitive and -resistant human hepatoma cell lines. Exp Cell Res 1996 226 133-139. 

Leipzig B. Cisplatin sensitization to radiotherapy of squamous cell carcinoma of the head and neck. AmerJSurg 1983 146 462 165. 

Zaffaroni N, Silvestrini R, Orlandi L, Bearzatto A, Gornati D, Villa R. Induction of apoptosis by taxol and cisplatin and effect on cell cycle-related proteins in cisplatin-sensitive and -resistant human ovarian cells. BrJ Cancer 1998 77(9) 1378-1385. 

Le Moguen K, Lineet H, Deslandes E et al. Comparative proteomic analysis of cisplatin-sensitive IGROVl ovarian carcinoma cell line and its resistant eounterpart IGROVI-RIO. Proteomics 2006 6 5183-5192. 

Furuta T, Ueda T, Aune G et al. Transcription-coupled nucleotide excision repair as a determinant of cisplatin sensitivity of human cells. Cancer Res 2002,62 4899 902. 

Fung MK, Cheung HW, Ling MT et al. Role of MEK/ERK pathway in the MAD2-mediated cisplatin sensitivity in testicular germ cell tumour cells. Br J Cancer 2006 95 475 84. 

Coronnello M, Marcon G, Carotti S, Caciagli B, Mini E, Mazzei T, Orioli P, Messori L (2000) Cytotoxicity, DNA damage, and cell cycle perturbations induced by two representative gold(III) complexes in human leukemic cells with different cisplatin sensitivity. Oncol Res 12 361-370... 

Over the years, it has become apparent that the antitumor activity of cisplatin is a consequence of several different cellular phenomena [24] [25]. DNA repair has been investigated as one factor that could influence cisplatin sensitivity, since failure to remove DNA lesions would allow them to persist and interfere with essential cellular systems. Several early studies provided evidence that trans-DDP was ineffective because its DNA adducts were repaired more efficiently than those of the d.v-isomer [4], This result... 

The Role of HMG-Domain Proteins in Modulating the Cisplatin Sensitivity of Cells... 

DNA cross-links [53] [54] [146], In vivo evidence for this model was provided by yeast double mutants. In this system the differential cisplatin sensitivity caused by inactivation of Ixrl was directly related to damage recognition and formation of the excision repair complex [140]. 

The endogenous HMG-domain proteins in HeLa cell free extracts do not seem to affect the relative rates of repair of cisplatin-DNA adducts [54] [62], Nevertheless, the hypothesis that HMG-domain proteins can enhance cellular sensitivity to cisplatin by blocking repair of the DNA adducts is still viable. Several HMG-domain proteins are specifically expressed in the testes ([146] and references cited therein), two of which, tsHMG and hSRY, inhibit the in vitro excision of cisplatin-DNA adducts at lower protein concentrations than any of the other HMG-domain proteins tested [54] [146], Selective expression of these or other such proteins in testicular tumors would provide an explanation for the unusual cisplatin sensitivity of this tumor type and the reduced repair of cisplatin-DNA adducts observed in testicular cell lines (discussed above). 

Additional studies using the same complexes in both cisplatin sensitive and resistant forms of U2-OS cells also showed differences in the cellular processing of the drugs both the free ligands and platinum complexes were rapidly found to accumulate in the nucleus, after uptake into the Golgi, which was hypothesized to be involved in transport of the platinum complexes out of the cells (56). In this set of studies, fluorescence imaging helped to illustrate the differences in the intracellular interactions of dinuclear platinum-anthraquinone complexes in different cell lines and in the different resistance profiles of A2780 and U2-OS resistant sub lines. 

Kellard LR, Abel G. Comparative in vitro cytotoxicity of Taxol and Tax-otere against cisplatin-sensitive and resistant human ovarian carcinoma cell lines. Cancer Chemother Pharmacol 1992 30 444-450. 

Trans complexes with the general formulas [PtCl2(L)2] (L = pyridine, N-methyl-imidazole and thiazole) or [PtCl2(L)(L )] (L = quinoline and V = RR SO where R = methyl and R = methyl, phenyl benzyl or L = quinoline and V = NH3) (Fig. 14.16) showed comparable activity to cisplatin and greater activity than trans-platin in cisplatin-sensitive and -resistant cell lines [51-54]. 

In cisplatin-sensitive and -resistant L1210 cell lines, the trans isomers exhibited greater activities than their cis counterparts [51-52]. 

These observations were further supported by the pharmacological studies. For example, in the ovarian cell line panel the acetate was equally active against a cisplatin-resistant cell line, CH1R, as against its cisplatin-sensitive counterpart, CHI. The mechanism of resistance to cisplatin in this cell line is repair of cisplatin-induced DNA damage. Also, [Au(OAc)2(damp)] had little activity against the ADJ/PC6 murine tumour, which is known to be particularly sensitive to compounds which cross-link DNA, such as cisplatin69. 

Comparisons of reactions of cis- versus fran -DDP with sulfur donors and other cellular components may afford some insight into their relative biological effects, however. /rans-DDP is much more reactive than the cis isomer with GSH (6, 27). Depletion of GSH with use of the inhibitor BSO had no effect on the cisplatin sensitivity of two human ovarian carcinoma cell lines, but made them 2.7 times more sensitive to trans-DY) (4). In a related finding, it was necessary to add 14 times more trans- than ds-DDP to cells in culture to achieve the same percent inhibition of in vivo SV40 DNA replication (23). These results suggest that part of the differential activity of these isomers in biological systems may arise from the differential reactivity of fran -DDP toward cellular components other than DNA. Thus trani-DDP could be more effectively inactivated prior to encountering DNA, or be better blocked as monofunctional platinum-DNA cross-links. 

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