Cisplatin activation

The development of new drugs capable of extending the clinical effectiveness of cisplatin necessitates a further increase in our knowledge of the molecular basis of cisplatin activity. 

In studies in vitro, caspases are involved in hypoxic [62,64] injury to RTE cells. Antimycin A-induced chemical hypoxia [64] or growth under hypoxic conditions results in increased caspase activity and pancaspase inhibition prevents hypoxia-induced DNA fragmentation and cell death in RTE cells. Partial ATP depletion of MDCK cells by antimycin A was also shown to result in apoptosis with marked increase in activation of caspase-8 and inhibition of caspases provided marked protection against antimycin A-induced cell death [65]. Exposure of freshly isolated RTE to hypoxia resulted in caspase activation and cell membrane damage [66]. In a related study, activation of caspase-3 during hypoxia or ATP depletion was shown to be accompanied by bax translocation and cytochrome c release [67]. As in ischemia, cisplatin activates the caspase cascade as well. Cisplatin induces selective and differential activation of caspases including executioner caspase-3... 

The stereochemistry of cisplatin and its trans-isomtr had been solved by Alfi-ed Werner (see chapter 1) in 1893. The traw-isomer, unlike cisplatin, is not active against tumors. Subsequent studies of the mechanism of the cisplatin activity by many groups demonstrated that it binds to DNA by... 

Miknyoczki SJ, Jones-Bolin S, Prichard S. Chemopotentiation of temozlomide, irinotecan and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor. 2003 2 371-382. 

Protein kinase C influenced cellular sensitivity to cisplatin. Activators of protein kinase C, such as phorbol 12,13-dibutyrate, enhanced the sensitivity of human small cell lung cancer H69 cells to cisplatin by 2-fold but had no effect on the sensitivity of cisplatin-resistant H69 cells to cisplatin (Busu et al. 1996). The maximum sensitisation was achieved with 10 nM phorbol 12,13-dibutyrate and blocked by down-regulation of protein kinase C with higher concentrations of phorbol 12,13-dibutyrate (1 jiM) or bryostatin 1 (0.1 p,M). H69 cells expressed conventional protein kinase Ca and -P, novel protein kinase C6, atypical protein kinase and -i, and novel/atypical protein kinase Cp,. A decrease in conventional protein kinase Ca and -P and an increase in novel protein kinase C6 were associated with the cisplatin-resistant phenotype. 

Formelli F, Cleris L (1993) Synthetic retinoid fenretinide is effective against a human ovarian carcinoma xenograft and potentiates cisplatin activity. Cancer Res 53 5374-5376... 

Sancho-Martinez SM, Piedrafita FI, Cannata-Andia JB et al (2011) Necrotic concentrations of cisplatin activate the apoptotic machinery but inhibit effector caspases and interfere with the execution of apoptosis. Toxicol Sd 122 73-85... 

A second family of carbohydrate-degrading enzymes, the lysozymes, produces synergistic antimetastatic activity when co-adrninistered with cisplatin [15663-27-1] to mice whose primary tumor had been surgically removed (51). 

When solutions containing the aqua complexes derived from cisplatin react with pyrimidines and other bases and are exposed to air, blue solutions (and solids) result [94], These are mixed-valence oligomers (n = 4). Some have anti-tumour activity but have not yet found clinical use. 

Figure 3.116 Platinum compounds studied for possible anti-tumour activity. I, ris-Dichlorodi-ammineplatinum(II) cisplatin, platinol NSC 119875 neoplatin platinex. II, a.s-Diammine(l,l-cyclobutanedicarboxylato)platinum(II) JM-8 paraplatin NSC 241240. Ill, Oxiplatin. IV, Tetraplatin. V, Amminediacetatodichloro(cyclohexylamine)platinum(IV). VI, cis-Dich oro-trans-dihydroxy-cis-bis(isopropylamine)platinum(IV) iproplatin JM-19 CHIP NSC 256927.

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],... 

Cisplatin — see Platinum, cw-dichlorodiammine-Cis-transisomerization, 1, 467 Citrate lyase activation... 

Bis(dicyclohexylammonium) bis(2,6-pyridinedicarboxylato)dibutylstannate is concluded to have sevenfold coordination at the Sn on the basis of its Sn CP/ MAS NMR chemical shift ((5 = —424.9 ppm). The assignment has been corroborated by crystal structure determination of its monohydrate, in which the Sn atom has frflMS-C2SnN04 PBP geometry (Sn-C = 204.0,206.7pm, C-Sn-C = 168.9°). One 2,6-pyiidinedicarboxylato group chelates to the Sn atom (Sn-O = 223.4,226.0 pm Sn-N = 227.9 pm), whereas the other binds through only one carboxyl end (Sn-O = 241.6, 244.1pm). The anhydrous compound displays higher in vitro antitumor activity than those of cisplatin and carboplatin (Table 7). ... 

When the antitumor activity of cisplatin was discovered, several research groups started to investigate the possible therapeutic applications of other metal-based, often organometallic, compounds. The organotin(lV) compounds that were first tested were those that were available or easily synthesized, like tri- or diorganotin(rV) halides. 

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