Cisplatin-resistant 5637 cell lines

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).

Similarly, McGowan et al. have synthesised a number of new ionic titanocene organometallic complexes (e.g. 4), which exhibit cytotoxicity against different human tumour cell lines including a cisplatin-resistant cell line [34]. 

An important point to note is that, in our detailed examination, the profile of antitumor activity of a simple dinuclear compound such as 1,1//,/ (n = 6) is generally similar to that of BBR 3464 (activity in cisplatin-resistant cell lines, enhanced activity in solid tumors classified as mutant p53 [3]) -what differs is the potency, producing the remarkable profile in Table 1. In the absence of major differences in aqueous chemistry the dramatically enhanced antitumor activity of BBR 3464 may be ascribed to this enhanced DNA affinity. 

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. 

Decreased uptake leads to lower intracellular drug concentrations. In many cisplatin-resistant cell lines, reduced accumulation was observed. The cisplatin membrane transport system is poorly understood, but studies on cisplatin-resistant cells with decreased drug accumulation have identified two membrane proteins that may be involved in uptake and efflux respectively a 48-kDa protein with decreased expression and a 200-kDa glycoprotein with increased expression. 

Increased DNA repair was observed in some cisplatin-resistant cell lines. For the 1,2-intrastrand addncts of cisplatin. 

Chauhan SS, Liang XJ, Su AW, Pai-Panandiker A, Shen DW, Hanover JA, Gottesman MM. Reduced endocytosis and altered lysosome function in cisplatin-resistant cell lines. Brit. J. Cancer 51. 2003 88 1327-1334. 

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. 

Fig 1. Example of microsatellite instability at the locus D17S796 in twenty subclones of the cisplatin resistant cell line A2780/cp70. The PCR products were fractionated on a 6% denaturing polyacrylamide gel and detected by autoradiography. The first four lanes show the M13 sequencing ladder used as a molecular-weight marker. Reproduced with authors permission. 

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. 

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. ... 

Table 3 In vitro evaluation of BBR3464 with the murine leukemia cell line (L1210) and the cisplatin-resistant cell line (L1210/DDP) measured as IC50 the required concentration to induce 50% inhibition of growth.

Table 4 Cytotoxic IC50 in the murine leukemia line L1210 can-cer cell line and its cisplatin-resistant cell line L1210/DDP.

The relative cytotoxicities of the Pt(II) carborane complexes are similar in both the cisplatin-sensitive and cisplatin-resistant cell lines. This clearly indicates that the mechanism of cytotoxicity of the Pt(II) carborane complexes is not affected by the cisplatin resistance mechanism(s). Preliminary in vitro DNA-binding experiments indicate that the complexes are capable of targeting plasmid DNA. 

Enhanced DNA repair this phenomenon has been observed in some cisplatin-resistant cell lines Most recently even a link was proposed with drug-induced tumor cell death, such as decreased apoptosis More details on resistance development can be found elsewhere... 

Pharmacological studies of gold(l) compounds have most recently focused on complexes containing new ligands that may enhance cytostatic activity and be particularly effective against cisplatin-resistant cell lines. Gold(l) compounds with l,2-bis(diphenylphosphine)ethane (dppe) and... 

---