Platinum resistant cell line

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).

Cells deficient in DNA repair are hypersensitive to cisplatin and some cisplatin-resistant cell lines show increased DNA repair and increased expression of the DNA. Platinum-induced DNA lesions are primarily repaired by the NER system. This system involves more than 20 proteins responsible for damage recognition, incision of the DNA strand on both sides of the lesion, removal of the damaged bases, and finally ligation by a DNA ligase. 

Gottesman MM. Trafficking and localization of platinum complexes in cisplatin-resistant cell lines monitored by fluorescence-labeled platinum. J. Cell. Physiol. 2005 202 635-641. 69. 

Dinuclear and trinuclear compounds represent a new class of platinum anticancer complexes and are among the most studied platinum compounds in antitumor chemistry. Many of these complexes circumvent cisplatin-resistance mechanisms.In contrast to cisplatin, the polynuclear complexes predominantly form interstrand cross-links. The dinuclear complex [ tra/25-PtCl(NH3)2 2 /u.-(H2N(CH2) NH2) ] + (17, Figure 9) is antitumor-active and shows no cross-resistance in cisplatin-resistant cell lines. Binding studies showed that DNA binding for this compound is different from that for cisplatin, as illustrated by the increased interstrand cross-linking. However, clinical testing was abandoned because of severe neurotoxicity. 

The platinum(iv) complexes, trans,tra s,trans-[Pt(N3)2(OH)2(MA)(Py)] (MA = methylamine, Py = pyridine) and trans,trans,trans-[Pt N3)2 Oli 2-(MA)(Tz)] (Tz = thiazole), have been tested as photoactivatable anticancer prodrugs. Their high photoreactivity is connected to the population of dissociative LMCT/d-d excited states, upon irradiation. These complexes bind to DNA in a very different manner from cisplatin according to the Authors, this could account for their high activity towards cisplatin-resistant cell lines. ... 

Decreased platinum uptake indeed in many cispladn-resistant cell lines reduced accumulation was indeed observed... 

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. 

Schmidt W, Chaney SG. Role of carrier ligand in platinum resistance of human carcinoma cell lines. Cancer Res 1993 53 799-805. 

Loh S Y, Mistry P, Kelland LR, Abel G, Harrap KR. Reduced drug accumulation as a major mechanism of acquired resistance to cisplatin in a human ovarian carcinoma cell line circumvention studies using novel platinum (II) and (IV) ammine/amine complexes. BrJ Cancer 1992 66 1109-1115. 

Kelland LR, Mistry P, Abel G, et al. Mechanism-related circumvention of acquired cis-diammine-dichloroplatinum(II) resistance using two pairs of human ovarian carcinoma cell lines by ammine/ amine platinum(IV) dicarboxylates. Cancer Res 1992 52 3857-3864. 

Gay M, Montana AM, Moreno V, Prieto M-J, Perez JM, Alonso C (2006) Studies of interaction of trichloro r 2-cis-N, N-dimethyl-l-[6-(N , N -dimethyl-ammoniummethyl)-cyclohex-3-ene-l-yl]-methylammonium platinum(II) chloride with DNA effects on secondary and tertiary structures of DNA. Cytotoxic assays on human ovarian cancer cell lines, resistant and non-resistant to cisplatin. Bioorg Med Chem 14 1565-1572... 

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