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 (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

Acquired drug resistance is a major drawback of using cisplatin in the treatment of cancer; however, analogs containing the 1,2-diaminocyclohexane (DACH) ligand can overcome this resistance. DACH can exist as the trans-1R,2R, trans-1S,2S or cis isomer, and we have examined whether specific isomers coordinated to a platinum(IV) center can modulate antitumor activities in murine tumor models in vivo. Ten isomeric series of DACH-Pt(IV) complexes were synthesized, each series containing a different combination of axial and equatorial ligands and varying only by the isomeric form of the DACH ligand. Among the ten series, seven clearly indicated superiority of the (R,R)-DACH-Pt(IV) complex against leukemia L1210/0 cells, while in three the R,R and S,S configurations gave similar efficacies which were better than that of the corresponding cis analog. In three out of the ten series, the antitumor activities of the S,S and cis complexes were similar, in six the cis analogs were the least effective, and in the remaining one the cis analog was superior to S,S. One series of complexes with axial chloro ligands and an equatorial 1,1-cyclobutanedicarboxylato group, which had produced the efficacy ranking R,R > cis > S,S in the L1210/0 model, gave S,S > R,R > cis against cisplatin-resistant L1210/DDP cells, R,R = S,S > cis against B16 melanoma cells, and R,R = S,S = cis against M5076 reticulosarcoma cells. The results demonstrate that profound variation can occur in antitumor activities among isomeric forms of the DACH-Pt(IV) complex. However, the (R,R)-DACH-Pt(IV) complexes appear to be of greater interest overall.
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PMID:Antitumor activity of isomeric 1,2-diaminocyclohexane platinum(IV) complexes. 818 34

The distribution and elimination kinetics of cis-diamminedichloroplatinum (II) (DDP) in female BDF1 mice bearing 6-day P388 leukemia were investigated in the presence and absence of procaine hydrochloride (P.HCl) exposure. DDP was administered as a single i.p. dose of 8 mg/kg in a 0.9% NaCl solution 6 days after tumor inoculum. P.HCl was administered as a single i.v. dose of 40 mg/kg immediately after DDP. The combined treatment with P.HCl produced marked changes in the plasma concentration-time profile of Pt. The unbound fraction of Pt was significantly increased both in the ascites fluid and plasma following DDP + P.HCl administration. P.HCl treatment induced a significant reduction (P < 0.01) in the rate constant of the protein-bound of Pt in plasma of tumored mice. Urinary excretion of Pt was unaffected by P.HCl, and there was no significant P.HCl-induced modification in the concentrations of Pt in the P388 leukemic cells. A statistically significant reduction of kidney and spleen Pt content was observed in female mice exposed to a dose of 8 mg/kg DDP + P.HCl. A similar reduction was observed in kidneys and testes of tumored mice receiving 16 mg/kg DDP along with 40 mg/kg P.HCl, which also showed lower renal and testicular cisplatin-DNA adducts after DDP + P.HCl than after DDP treatment. Potential explanations for the ability of P.HCl to interfere with the pharmacokinetics and biodistribution of DDP are discussed.
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PMID:Cis-diamminedichloroplatinum (II)-procaine pharmacokinetic interaction in mice bearing P388 leukemia. 823 29

Two ruthenium(II) complexes, characterised by the presence of dimethylsulphoxide ligands, were investigated in comparison to cisplatin on mouse P388 leukaemia and on a subline made resistant to cisplatin (P388/DDP). Both cis- and trans-RuCl2(DMSO)4 significantly prolonged the survival time of leukaemic mice, independently of the tumour line used. Unlike cisplatin, the prolongation of life-span of tumour-bearing hosts caused by ruthenium complexes was not supported by a parallel inhibition of the number of tumour cells in the treated hosts, as evidenced by tumour cell count in the peritoneal cavity and by vivo-vivo bioassays of blood samples and of whole brains. Thus, cis- and trans-RuCl2(DMSO)4 appear capable of preventing leukaemic spread into the central nervous system also when the number of tumour cells in the peritoneal cavity and in the blood stream is as high as in untreated controls. When the drug-induced DNA damage was investigated by modifying double stranded DNA and identifying the lesions able to inhibit DNA synthesis in vitro, trans-RuCl2(DMSO)4 and, to a lesser extent, cis-RuCl2(DMSO)4 formed blocking lesions at the same sites of cisplatin; nevertheless, the mechanism of antitumour activity of ruthenium complexes appears to be different from that of cisplatin for the absence of any relationship between cytotoxicity and prevention of leukaemic dissemination into the central nervous system. These data indicate that the activity of cis- and trans-RuCl2(DMSO)4 on the P388 leukaemia is characterised by the lack of cross-resistance with cisplatin and by the alteration of the metastasising behaviour of leukaemic cells which lose their natural capacity to invade the central nervous system.
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PMID:Anti-leukaemic action of RuCl2 (DMSO)4 isomers and prevention of brain involvement on P388 leukaemia and on P388/DDP subline. 826 Feb 45

Concurrent administration of para-aminobenzoic acid (PABA) reduced the toxicity of cis-diamminedichloroplatinum(II) (DDP) in a dose-related manner in rats. When administered i.p. simultaneously with 7.5 mg/kg DDP, PABA (100 mg/kg) significantly reduced plasma urea nitrogen (PUN) and plasma creatinine levels as well as DDP-induced weight loss. Increasing doses of PABA (25, 50 and 100 mg/kg) correlated with progressively better parameters of renal activity and body wt and with lower levels of platinum in plasma and tissues in rats killed 5 days after drug administration. The formation of cisplatin-DNA adducts, the total platinum levels in kidney and testes and the DDP-induced tumor response were investigated in the presence and absence of PABA exposure in mice bearing P388 leukemic cells. Renal and testicular DNA-adducts in mice treated i.p. with 16 mg/kg DDP in normal saline were higher than those observed in mice receiving the same protocol and added PABA. Analysis of tissue platinum content demonstrated significantly lower platinum levels both in kidneys (P < 0.05) and testes (P < 0.01) of mice receiving DDP and PABA in normal saline compared to those receiving only DDP in normal saline. PABA did not affect the in vivo and in vitro antitumor activity of DDP against P388 leukemia, and there was no significant PABA-induced modification in the concentration of platinum both in the tumor cells and in DNA samples isolated from P388 leukemic cells of DDP-treated mice. We conclude that PABA may be a promising compound for reducing DDP-toxic side effects, including nephrotoxicity, without compromising its antitumor activity.
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PMID:Para-aminobenzoic acid suppression of cis-diamminedichloroplatinum(II) nephrotoxicity. 826 32

Serum-free growth of Ewing's sarcoma (ES) and primitive peripheral neuroectodermal tumour (pPNET) cell lines was achieved by supplementing a basal medium with insulin-like growth factor-I (IGF-I). These cultures were used to investigate the sensitivity of 3 ES (EW-2, RD-ES, SK-ES-1) and 3 pPNET (SIM-1, KAL, SAL) cell lines to a panel of anti-tumour agents in short-term (48-h) proliferation assays. Of the four cytostatic drugs included in the currently used multi-drug regimens, cyclophosphamide, doxorubicin and actinomycin-D inhibit the proliferation of the cell lines with high efficacy, whereas the vinca alkaloids were less effective. Cisplatin, etoposide, mitomycin-C and mitoxanthrone were also found to have a high inhibitory activity in this in vitro ES/pPNET system. The most remarkable effect was observed for cytosine arabinoside (ARA-C), which gave a half-maximal inhibition at drug concentrations approximately 5000 times below the clinical peak plasma concentrations (250 micrograms/ml). The ARA-C sensitivity of ES and pPNET cell lines is comparable with the established ARA-C sensitivities of leukaemia-derived cells. The different ES and pPNET cell lines showed a rather uniform response to the different cytostatic drugs with decreased sensitivity of individual pPNET cell lines to vinblastin, ARA-C and mitoxanthrone. Modulation of the IGF-I/IGF-I receptor/IGF-I binding protein system, which seems to constitute an important stimulator of cell growth in neuroectoderm-derived or -related tumours, can be used to enhance the drug sensitivity of the tumour cells in vivo or in vitro therapeutic procedures. According to our results, serum-free conditions for autologous bone marrow purification are expected to result in significantly increased chemosensitivity of ES and pPNET cells in response to anthracyclines and cisplatin.
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PMID:Insulin-like growth factor-I-dependent growth and in vitro chemosensitivity of Ewing's sarcoma and peripheral primitive neuroectodermal tumour cell lines. 838 Jun 98

Cisplatin, mitomycin C and 5-fluorouracil were given a 55-year-old woman for an unresectable gastric cancer, and successful radical gastrectomy was performed. Postoperative adjuvant immunochemotherapy using UFT and PSK was continued for about 4 years and 4 months. Pancytopenia was observed at 5 years after the treatment and then marked leucocytosis was noted. She also showed complications of general fatigue, appetite loss etc. A secondary acute leukemia associated with eosinophilia was diagnosed by peripheral blood examinations, showing WBC, 122,400: blast, 37.5 % and eosinophil, 41%. Results also showed atypia and pseudo-Pelger nuclear abnormality of eosinophil, high positive stain of cell myelogenic cell surface marker, many numeral and structural abnormalities of chromosomal analysis, etc. From the above results, it was suggested that the leukemia might be induced by previously performed chemotherapy. The patient died about 2 months following its onset.
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PMID:[A case of secondary leukemia induced by chemotherapy with a CDDP-based regimen for gastric cancer 5 years following radical resection]. 842 78

Among various molecular mechanisms of cell resistance to antitumor agents such as cisplatin, it has recently been suggested that enhanced DNA-repair activity might be involved in the resistant phenotype of cell lines. Mouse leukemia-cisplatin-resistant cell lines L1210/10 (adapted in vitro) and L1210/DDP (adapted in vivo) have been reported to exhibit an increase DNA-repair activity, as determined by host-cell reactivation after transformation with damaged plasmids. In this paper, excision-repair activity was monitored by an in-vitro assay allowing quantification of DNA-repair synthesis in cell extracts from resistant and sensitive parental cells (L1210/10 versus L1210/0 and L1210/DDP versus L1210/S). Experimental conditions for optimal repair-synthesis activity were found to be different from these reported with human cell-line extracts. L1210/S sensitive cell line, grown in vivo by a weekly intraperitoneal graft in mice, displayed a repair activity about fourfold lower than the same cell line maintained in vitro or than L1210/0 cell grown in vitro. The repair activity was found similar in a L1210/10 and L1210/0 cell lines, but it was enhanced in L1210/DDP resistant cell line when compared with its parental line.
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PMID:DNA excision-repair synthesis is enhanced in a murine leukemia L1210 cell line resistant to cisplatin. 843 4

The inhibition of [14C]thymidine incorporation into DNA of tumor and normal tissues of L1210-leukemia-bearing mice by single doses of cis-diamminedichloroplatinum (II) (cisplatin, cis-DDP) and two newly synthesized platinum (II) complexes containing as ligands dimethyl aminomethylphosphine oxide (complex I) and methyl bis(aminomethyl)phosphine oxide (complex II) was studied and used as an indication of drug toxicity. All three complexes caused selective inhibition of precursor incorporation in L1210 cells as compared to host tissue cells. cis-DDP caused a complete block of incorporated thymidine in tumor cells during more than 48 h, whereas in intestinal mucosa and bone marrow reverse inhibition was observed. In spleen, liver and kidney the inhibition was about 50% and endured up to 96 h without reversal. Complex I treatment of L1210 cells resulted in an earlier recovery of thymidine incorporation into DNA in comparison with cis-DDP. Towards all other normal tissues compound I was less toxic than cis-DDP. Unlike cis-DDP and complex I, complex II was less active against L1210 cells and most toxic against bone marrow and kidney.
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PMID:Inhibition of DNA synthesis in different tissues of L1210-leukemia-bearing mice by new platinum (II) complexes. 844 64

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


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