Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tetraplatin (tetrachloro[d,l-trans]1,2-diaminocyclohexane platinum IV (TTP)) is a new platinum analogue active against L1210 murine leukemia that is resistant to cisplatin (diamminedichloroplatinum II (DDP)). Since nephrotoxicity is a significant problem with DDP therapy, we compared the effects of equitherapeutic doses of TTP and DDP on renal structure and function in rats. We also studied the effects of the 2 platinum compounds on the distribution and excretion of gentamicin (GENT), an antibiotic that is excreted solely by the kidneys. Rats treated intravenously with 2.85 mg/kg of DDP on days 1, 5 and 9 had significantly different plasma urea nitrogen (BUN) levels and creatinine clearance rates on day 16 than those given the same doses of TTP. The renal function of TTP-treated rats did not differ from that of controls or rats given only GENT. Twenty-four hours after a single GENT dose (given on day 15), DDP-treated rats had higher GENT concentrations in the plasma, liver and spleen than rats given GENT alone. TTP-treated rats had higher GENT levels only in the spleen. DDP-treated rats retained a higher percentage of the injected platinum in the renal cortex than those treated with TTP. Light microscopic examination of renal tissue showed necrotic cells and dilated tubules in the proximal tubules of DDP-treated rats while the kidneys of TTP-treated rats were largely indistinguishable from those of controls. Thus, our results indicate that the distribution of platinum in the kidneys differs between rats treated with TTP and those treated with DDP. This may partly explain the considerably lower nephrotoxicity of TTP.
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PMID:A comparison of the effects of tetraplatin and cisplatin on renal function and gentamicin pharmacology in rats. 258 64

Tetrachloro(d,l-trans)1,2-diaminocyclohexane platinum (IV) (tetraplatin), a new platinum analogue, showed greater therapeutic efficacy after i.p. administration than either cis-dichlorodiammineplatinum (II) (cisplatin) or cis-diammine-1,1-cyclobutanedicarboxylate platinum (II) (carboplatin) in mice bearing i.p. implanted L1210 leukemia. At an optimal dose of 5.7 mg/kg/injection given as a single dose on days 1, 5, and 9, tetraplatin increased the median life span over controls by more than 566% with 5 of 8 long-term (50-day) survivors. In contrast, cisplatin at the same optimal dose increased survival by 186% with 2 of 8 long-term survivors, and carboplatin at an optimal dose of 75.6 mg/kg/injection increased survival by only 120% with no long-term survivors. Tetraplatin also was more effective than cisplatin when treatment was delayed until days 3, 7, and 11 after i.p. implant. A combination of tetraplatin and Adriamycin in mice bearing i.p. implanted L1210 leukemia produced more long-term survivors over a wider range of doses than could be achieved with either drug alone. Tetraplatin at 5.7 mg/kg/injection and Adriamycin at 3 mg/kg/injection on days 1, 5, and 9 increased survival by more than 566% with 8 of 8 50-day survivors. Using the same treatment schedule, combinations of tetraplatin with either cisplatin, carboplatin, daunomycin, or 5-fluorouracil did not produce therapeutic efficacy greater than that seen with tetraplatin alone. The in vitro cellular uptake of platinum by L1210 cells at 37 degrees C was about 4-fold higher after exposure to tetraplatin compared to cisplatin following a 2-h incubation at the two concentrations examined (2.5 and 5 micrograms/ml). Comparative pharmacological studies were performed in rats at a single dose of 3 mg/kg i.v. The t1/2 beta for total platinum in plasma was 29.10 h (7.47 h for unbound platinum) after the administration of tetraplatin and 23.70 h (13.09 h for unbound platinum) after cisplatin. By 48 h the urinary excretion of platinum after tetraplatin and cisplatin was 30.1% and 41.4%, respectively. Tissue distribution of platinum was similar after either complex. Thus, tetraplatin has similar pharmacological properties to cisplatin and like cisplatin is a candidate for combination chemotherapy. However, tetraplatin may be superior to cisplatin in some therapeutic situations based on its greater efficacy against selected tumors.
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PMID:Therapeutic and pharmacological studies of tetrachloro(d,l-trans)1,2-diaminocyclohexane platinum (IV) (tetraplatin), a new platinum analogue. 316 2

Tetraplatin (Ormaplatin) has good antitumor activity against some cisplatin-resistant cells and is currently being studied in clinical trials. We have studied the effect of extracellular reduced glutathione (GSH) on the cytotoxicity and biochemical pharmacology of tetraplatin in L1210 leukemia cells. Parent L1210/0 cells were exposed to tetraplatin for 2 hr with or without GSH in Hanks' balanced salt solution (HBSS), and cytotoxicity was assessed by a soft agar clonogenic assay. GSH (10 or 100 microM) increased tetraplatin (10 microM)-induced cell kill by about 2 logs; concentrations of the thiol 10-fold below or above these levels increased cell kill to a lesser degree. GSH-mediated increases in the cytotoxicity of tetraplatin were also observed against cisplatin-resistant L1210/DDP and tetraplatin-resistant L1210/DACH cells. An equimolar concentration of 1,2-diaminocyclohexane-platinum(II) dichloride [DACH-Pt(II)Cl2] alone was as cytotoxic as the combination of tetraplatin and GSH. Intracellular accumulations of tetraplatin in both L1210/0 and L1210/DDP cells were increased by GSH, whereas in L1210/DACH cells platinum uptake decreased in the presence of the thiol. Reactions between tetraplatin and salmon sperm DNA in the presence or absence of GSH (1 or 100 microM), performed at 37 degrees in HBSS, revealed that levels of total and interstrand DNA-platinum adducts were minimal in the absence of GSH, whereas in the presence of GSH DNA adducts of tetraplatin were substantial and similar to those seen with DACH-Pt(II)Cl2. Tetraplatin (10 microM) incubated at 37 degrees in HBSS with GSH (10 microM-1 mM) was reduced chemically to the DACH-Pt(II) species within 5 min; a 200-microM tetraplatin solution required a GSH concentration of at least 100 microM for substantial reduction to occur. This chemical reduction of tetraplatin appears to be a prerequisite for its biological activity. Thus, extracellular GSH can modulate the biological activity of tetraplatin, and the combination may prove useful in specific clinical applications, such as intracavitary platinum therapy.
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PMID:Glutathione-mediated modulation of tetraplatin activity against sensitive and resistant tumor cells. 818 78

Some platinum complexes contain 1,2-diaminocyclohexane (DACH) as a stable carrier ligand, which can exist as the R,R-, S,S- and cis-isomers. Tetraplatin, for instance, is a mixture of R,R- and S,S-DACH-Cl4-Pt(IV). We have examined each of the three individual isomers of DACH-Cl4-Pt(IV) with respect to cytotoxicity, uptake of platinum and total DNA-platinum in three murine leukemia L1210 (cisplatin-sensitive L1210/0, 50-fold cisplatin-resistant L1210/DDP and 36-fold tetraplatin-resistant L1210/DACH) and human ovarian carcinoma A2780 (cisplatin-sensitive) and A2780cp (8-fold cisplatin-resistant) cell lines. Against A2780, A2780cp and L1210/DDP cell lines, the R,R-isomer was the most potent followed by the S,S-isomer and then the cis-isomer. However, the three isomers demonstrated similar IC50 values against the L1210/0 and L1210/DACH cell lines. The cis-isomer demonstrated cross-resistance (9- to 20-fold) to cisplatin in L1210/DDP and A2780cp cell lines. On the other hand, R,R- and S,S-isomers demonstrated minimal (2- to 4-fold) cross-resistance against these tumor models. Intracellular platinum accumulation over a 2 h period at 40 microM drug concentration was significantly (p < 0.05) greater for the R,R-isomer than the cis-isomer in L1210/0 (122 versus 101 ng Pt/mg protein) and L1210/DDP (73 versus 50) cell lines, while no difference was observed in L1210/DACH cells (55 versus 56). In L1210/DDP cells, total DNA-bound platinum was significantly (p < 0.05) greater for the R,R-isomer compared with the cis-isomer (10.3 versus 7.5 ng Pt/mg DNA).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential cytotoxicity, uptake and DNA binding of tetraplatin and analogous isomers in sensitive and resistant cancer cell lines. 849 Feb 3