Preparation and cytotoxicity of cisplatin-containing liposomes

We encapsulated cisplatin into stealth pH-sensitive liposomes and studied their stability, cytotoxicity and accumulation in a human small-cell lung carcinoma cell line (GLC4) and its resistant subline (GLC4/CDDP). Since reduced cellular drug accumulation has been shown to be the main mechanism responsible for resistance in the GLC4/CDDP subline, we evaluated the ability of this new delivery system to improve cellular uptake. The liposomes were composed of dioleoylphosphatidylethanolamine (DOPE), cholesteryl hemisuccinate (CHEMS), and distearoylphosphatidylethanolamine-polyethyleneglycol 2000 (DSPE-PEG2000) and were characterized by determining the encapsulation percentage as a function of lipid concentration. Among the different formulations, DOPE/CHEMS/DSPE-PEG liposomes (lipid concentration equal to 40 mM) encapsulated cisplatin more efficiently than other concentrations of liposomes (about 20.0 percent, mean diameter of 174 nm). These liposomes presented good stability in mouse plasma which was obtained using a 0.24-M EDTA solution (70 percent cisplatin was retained inside the liposomes after 30 min of incubation). Concerning cytotoxic effects, they are more effective (1.34-fold) than free cisplatin for growth inhibition of the human lung cancer cell line A549. The study of cytotoxicity to GLC4 and GLC4/CDDP cell lines showed similar IC50 values (approximately 1.4 æM), i.e., cisplatin-resistant cells were sensitive to this cisplatin formulation. Platinum accumulation in both sensitive and resistant cell lines followed the same pattern, i.e., approximately the same intracellular platinum concentration (4.0 x 10-17 mol/cell) yielded the same cytotoxic effect. These results indicate that long-circulating pH-sensitive liposomes, also termed as stealth pH-sensitive liposomes, may present a promising delivery system for cisplatin-based cancer treatment. This liposome system proved to be able to circumvent the cisplatin resistance, whereas...

Effect of treatment schedule on the toxicity andpharmacokinetics of cisplatin-doxorubicin combination in Rabbits

The effects of treatment schedule on the interaction between cisplatin [CDDP] and doxorubicin [DOX] were studied in male New Zealand rabbits. Rabbits were divided into three groups., five animals each. Group I received the two drugs simultaneously while group II animals were treated sequentially with DOX one hour post CDDP administration. A third control group was injected with normal saline. Both drugs were injected as an IV. bolus of equal doses, 4 mg/kg each, and their concentrations were determined by spectrofluorometry and flameless atomic absorption spectrometry, respectively. Toxicity was assessed biochemically by estimating indices of nephrotoxicity and tissue peroxidative alterations in terms of malondialdehyde MDA production levels and non-protein sulfhydryl group contents as well as histopathological examination of kidney, heart and liver tissues. Both treatment schedules showed significant increases in serum creatinine and urea levels [p<0.01]. Also, both treatment schedules showed significant increase in MDA production levels and depletion of non-protein sulthydryl group contents in the kidney, heart and liver tissues [p<0.001]. All previous changes were aggravated with sequential administration of CDDP-DOX combination in comparison with the simultaneous one. Furthermore, histopathological examination revealed that sequential CDDP-DOX combination produced significant pathological changes in the rabbits kidney, heart and liver tissues in comparison with those animals treated simultaneously. These results were confirmed by studying the phaimacokinetics of both drugs. The plasma concentration time data for both drugs were fitted into an open two compartment model. DOX pharmacokinetics was significantly altered in the sequentially treated group [p<0.001]. The distribution and elimination half lives for the simultaneously and sequentially treated groups were 0.06 +/- 0.0095 h vs 0.104 +/- 0.0287 hand 3.48 +/- 0.5 11 h vs 18.96 +/- 3.7 h, respectively. The total body clearance in the two groups were 17.64 +/- 1.28 mI/min and 3.31 +/- 0.68 mI/min, respectively. The mean resident time [MRT] and total area under the curve [AUC] were 4.77 +/- 0.689 h and 3.8 +/- 0.26 pg/mI x h vs 26.82 +/- 5.34 h and 20.92 +/- 4.76 pg/mI x h, respectively. The volume of distribution at steady state [V] was 5.02 +/- 0.58 L vs 5.15 +/- 0.291 L, respectively. The pharmacokinetics of CDDP was not affected by changing the treatment schedule [p>0.05]. The only significant change observed was in the distribution half-life, where it appeared to be 0.09 1 +/- 0.054 h and 0.33 1 +/- 0.047 h for simultaneously and sequentially treated animals, respectively. In conclusion, sequential administration of CDDP at one hour prior DOX injection was associated with dramatic changes in the pharmacokinetics of DOX. This might contribute to aggravation of DOX-induced cardiotoxicity as well as hepatorenal toxicity of both drugs

Situaçäo atual da quimioterapia intraperitoneal em câncer de ovário avançado / Present outlook of intraperitoneal drug therapy in advanced ovarian neoplasm

O artigo revisa o tema, com ênfase especial a utilizaçäo do cisplatino