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

Concurrent administration of sodium thiosulfate reduced the toxicity of cis-dichlorodiammineplatinum(II) (DDP) in a dose-related manner in mice. Sodium thiosulfate protected mice against an otherwise lethal dose of DDP (20 mg/kg), and reduced DDP-induced weight loss. Sodium thiosulfate (800 mg/kg) injected within 1 hour before or 1/2 hour after DDP blocked nephrotoxicity as measured by a rise in BUN, an increase in kidney weight, and medullary hemorrhage. In culture, sodium thiosulfate markedly reduced the toxicity of DDP to mouse colony-forming units. Concurrent injection of sodium thiosulfate partially reduced the antitumor activity of DDP. The therapeutic dose range of DDP was expanded, but the maximum increase in lifespan of mice bearing L1210 leukemia was reduced by 40%. Sodium thiosulfate offers the possibility of systemic protection against the cytotoxicity of regionally administered DDP in man.
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PMID:Effect of sodium thiosulfate on cis-dichlorodiammineplatinum(II) toxicity and antitumor activity in L1210 leukemia. 719 78

The cross-linking of DNA by cis-diamminedichloroplatinum(II) (cis-DDP) has been studied in a murine leukemia L1210 line (L1210/0) and a 30-fold resistant subline (L1210/DDP2) utilizing the technique of alkaline elution. The kinetics of cross-link formation were similar in both cell lines. After 1-h treatment with cis-DDP, cross-linking continued to increase to a maximum at 12 h posttreatment. Although cross-linking decreased by 24 h some lesions were seen to persist. After 72 h interstrand cross-links were completely removed by both cell lines, however 50% of the DNA-protein cross-links still remained in the sensitive cells even though they were undetectable in the resistant subline. To correlate cross-linking with cytotoxicity, a range of drug concentrations were used for concomitant growth inhibition studies and alkaline elution analyses. In addition to the 30-fold resistant subline, two other sublines developed in our laboratory which show 20- and 50-fold resistance to cis-DDP were included in these determinations. All the resistant sublines exhibited the same degree of cross-linking at the same applied drug doses although these doses elicited markedly different cytotoxicities; cross-linking varied only with applied drug concentrations. The degree of cross-linking in L1210/0 was also directly related to the dose of cis-DDP. However, the sensitive cell line displayed equivalent total cross-linking at a 5-fold lower applied dose. This may implicate an uptake phenomenon as a contributor to resistance. However, such a phenomenon can account for only part of the resistance observed as there existed 6-fold more total cross-links and 9-fold more interstrand cross-links in L1210/DDP2 at doses that were equitoxic to L1210. This suggests the existence of a more critical cytotoxic lesion that was not detectable by alkaline elution, probably interstrand cross-links. Resistance could be due to a differential removal of these lesions.
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PMID:The significance of DNA cross-linking to cis-diamminedichloroplatinum(II)-induced cytotoxicity in sensitive and resistant lines of murine leukemia L1210 cells. 719 96

Apoptosis is characterized by typical morphological changes and most frequently fragmentation of DNA into oligonucleosome-size fragments. In order to investigate whether an alteration in the mechanisms involved in the process of apoptosis could contribute to cellular resistance, induction of apoptosis was studied in a cisplatin-resistant cell line (L1210/DDP) derived from a L1210 murine leukemia cell line (L1210/0). Treatments of the parental L1210/0 cell line with two DNA damaging agents (cisplatin and 5-azacytidine) or a protein kinase C inhibitor (staurosporine) led to biochemical events characteristic of apoptosis (as determined by the cell morphology and the oligonucleosomal DNA fragmentation). In contrast, the cisplatin-resistant L1210/DDP subline, which was cross-resistant to 5-azacytidine, did not exhibit any DNA fragmentation or morphological changes typical of apoptosis when exposed to toxic concentrations of either cisplatin or 5-azacytidine. The failure of these cells to undergo apoptosis upon cisplatin or 5-azacytidine exposure has been correlated with the lack of a nuclear endonuclease activity present in wild-type cell nuclei. However, staurosporine, which exerted the same toxicity on both cell lines, induced the internucleosomal DNA fragmentation and morphological features of apoptosis in both of them. This indicates that a functional pathway for apoptosis is preserved in the resistant cells. The induction of this pathway can be correlated with the presence of a cytoplasmic endonuclease activity whose specificity seems different from that operating in L1210/0 cells in terms of cation and pH dependence. Therefore, in these cell lines, different endonucleases are possibly involved in apoptosis. In response to treatment with drugs having different targets, the apoptotic cell death may operate through different signaling pathways, one of them being possibly defective in the L1210/DDP-resistant cells.
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PMID:Cisplatin resistance in a murine leukemia cell line is associated with a defective apoptotic process. 753 90

In the present paper we present data on the synthesis, crystal structure and biological activity of bis(dipyridamole) tetrachloroplatinate(II).dipyridamole.dihydrate, [dpmH]2 PtCl4.dpm.2H2O. The crystals are Triclinic P1 with a = 11.490(2) A, b = 13.630(2) A, c = 15.81(1) A, a = 100.97(2) degrees, beta = 100.89(3) degrees, gamma = 112.35(1) degrees, Z = 1, M = 1885.9, Dx = 1.46 g/cm3, MoK alpha (lambda = 0.71069 A), mu = 0.0184 mm-1, R = 4.4%, Rw = 5.0%, 3231 (1 > 2 sigma (I)). The structure is stabilized by a hydrogen-bonding network. It was observed that although dpm alone is not able to alter the electrophoretic mobility of pUC8 DNA forms, the synthesized Pt-dpm compound substantially modifies the DNA conformation since it significantly alters the electrophoretic mobility of nicked and closed circular forms of pUC8 DNA. However, the alteration in mobility of pUC8 DNA induced by this compound upon binding is lower than that induced by cis-DDP. The analysis of the antiproliferative activity of the Pt-dpm salt against MDA-MB 468 (breast carcinoma) and HL-60 (leukemia) human cancer cells showed that this compound has ID50 values of 0.87 microM and 0.65 microM, respectively. Interestingly, it was found out that although the dpm molecule does not present any significant antiproliferative activity, the ID50 values of Pt-dpm are about 3-fold and 7-fold lower than those of cis-DDP and K2PtCl4, respectively. Altogether the biological data suggest that in Pt-dpm a synergic effect between cation and anion is produced.
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PMID:Synthesis, crystal structure, and biological activity of a Pt-dipyridamole salt. 784 86

The in vitro and in vivo antitumor activity of a new antitumor platinum complex, cis-malonato[(4R, 5R)-4,5- bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (SKI2053R, NSC D644591), were evaluated and compared with those of cisplatin (CDDP) and carboplatin (CBDCA) using murine tumors. SKI 2053R was highly active in vitro against both L1210 murine leukemia and its CDDP-resistant subline, L1210/DDP; the relative resistances were 20.0-, 14.5-, and 2.7-fold for CDDP, CBDCA, and SKI 2053R, respectively. SKI 2053R showed activity comparable with or superior to either CDDP or CBDCA in mice implanted with L1210. In mice implanted with L1210/DDP, as compared with CBDCA, SKI 2053R showed high values for the percentage of treated survivors relative to controls and for numbers of cured mice, whereas CDDP had virtually no activity. In mice implanted with P388, all three drugs were highly active, but the intensity of activity was shown to be ranked in the following order: SKI 2053R > CDDP > CBDCA. The antitumor activity of SKI 2053R against Lewis lung carcinoma was comparable with that of both CDDP and CBDCA. The antitumor activity of SKI 2053R was further investigated against two human tumor xenografts, KATO III (stomach adenocarcinoma) and WiDr (colon adenocarcinoma), implanted s.c. in nude mice and was compared with that of CDDP. In SKI 2053R-treated groups, the time required for a mean tumor weight of 1,000 mg was 33.1 days in KATO III xenografts and 35.0 days in WiDr xenografts as compared with 30.2 and 27.2 days in CDDP-treated groups, respectively. SKI 2053R achieved growth-inhibition rates comparable with those of CDDP against KATO III (65% versus 59%) and WiDr xenografts (64% versus 54%) on day 35. These results indicate that SKI 2053R is an attractive candidate for further development as a clinically useful anticancer drug.
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PMID:Antitumor activity of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2- isopropyl-1,3-dioxolane]platinum(II), a new platinum analogue, as an anticancer agent. 785 Sep 28

Diethyldithiocarbamate (DDTC) and N-acetylcysteine (NAC) are nucleophile sulfur-containing compounds which can protect the platinum-induced nephrotoxicity. Combinations of cis-diamminedichloroplatinum(II) (cis-DDP) and DDTC or NAC were tested on the leukemia L1210 and melanoma B 16 tumor models. Nephrotoxicity of cis-DDP alone and in combination with DDTC or NAC was evaluated. On both of the investigated tumor models clastogenic effects in bone marrow cells were detected. DNA synthetic and mitotic activity of L1210 cells in vivo were evaluated by 3H-thymidine incorporation and cytogenetic analysis. Amelioration of the platinum induced nephrotoxicity and preservation of the antitumor activity of cis-DDP through combined application with DDTC or NAC were obtained at the L1210 model. Maximal inhibition of the DNA synthesis in L1210 cells was detected with the cis-DDP treatment. The sulfurcontaining nucleophiles DDTC or NAC could modulate the inhibitory effect of cis-DDP on the incorporation of 3H-thymidine into the nuclei of L1210 cells. Enhanced mitotic activity was detected during cytotoxic therapy with cis-DDP. Cis-DDP alone and in combination with DDTC or NAC caused a significant growth inhibition on the s.c. tumor of the melanoma B16 bearing mice. Two times better therapeutic results at this model were obtained with cis-DDP alone (T/C = 234.09%, T/C = 136.36% for cis-DDP+DDTC and T/C = 151.14% for cis-DDP+NAC). The usefulness of DDTC or NAC as adjuvants in the platinum based chemotherapy of human cancers have been discussed. Clastogenic effect and antitumor activity are probably connected and it is supposed that the reduction of the genotoxicity could lead to a decreased antitumor activity of the platinum complex.
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PMID:Antitumor, nephrotoxic and clastogenic effect of cis-DDP with DDTC or NAC. 785 94

A platinum(II) and three platinum(IV) ammine/cycloalkylamine homologous series, the latter possessing either chloro, acetato or hydroxo axial ligands, were evaluated for efficacies in mice bearing tumor cells sensitive (leukemia L.1210/0 and reticulosarcoma M5076) or resistant to cisplatin (L1210/DDP) and tetraplatin (L1210/DACH). Within each series, which contained four homologs, potency increased (optimal dose decreased) as alicyclic ring size increased incrementally from cyclopropane to cyclohexane. All analogs were active at maximally tolerated doses against L1210/0 (%T/C = 125-426), with good associated therapeutic ratios of 2 to > 8 that, like the therapeutic index, provided indications of the drug's safety margin. Most complexes had activities that were similar to cisplatin (%T/C = 239) and tetraplatin (%T/C = 310). Antitumor activities were seen for all four platinum(II) complexes against L1210/DDP cells (%T/C = 133-167). In the three platinum(IV) series, on the other hand, only cyclopentane (C5) and cyclohexane (C6) analogs met or exceeded the minimum criterion for activity. These activities were similar to that seen with the positive control agent tetraplatin (%T/C = 133), but higher than that of cisplatin (%T/C = 94). Long-term survivors, which were frequently observed with these complexes in the L1210/0 model, were also seen in the L1210/DDP model, but to a lesser extent. Against L1210/DACH cells, which were sensitive to cisplatin (%T/C = 155), but resistant to tetraplatin (%T/C = 113), the C5 and C6 congeners in the platinum(IV) series were effective with %T/C in the range 148-189, while corresponding members in the platinum(II) series were only marginally active. In the solid M5076 model, complexes C5 in platinum(II) and in the acetato- and hydroxoplatinum(IV) series, and C6 from the hydroxo-platinum(IV) series, were as effective or more effective than cisplatin, which itself gave a tumor growth delay of 27.5 days. In summary, the results indicate that alicyclic ring size and, in the platinum(IV) series, axial ligand, are important modulators of efficacies of ammine/cycloalkylamine platinum congeners in both sensitive and platinum-resistant models. However, the cyclopentylamine or cyclohexylamine carrier ligand with acetato or hydroxo axial ligands in the platinum(IV) configuration are optimal combinations for circumventing both cisplatin and tetraplatin resistances.
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PMID:Tetravalent platinum complexes with ammine/amine carrier ligand configuration: circumvention of platinum resistance in vivo. 788 Mar 75

Three homologous series, each differing from the other in the coordinated amine ligand class, namely alicyclic, heterocyclic or isoaliphatic, were highly effective against wild-type murine leukemia L1210/0 cells in vivo (T/C = 171%-426% at optimal doses). Of the 13 complexes comprising the three series, 3 were inactive in the cisplatin-resistant L1210/DDP model, but the other 10 maintained good efficacy (T/C = 131%-167%). Long-term survivors, frequently observed with these complexes in the L1210/0 model, were also seen in the L1210/DDP model but to a lesser extent. In the homologous alicyclic series, which contained six analogs, as the alicyclic ring size increased, potency against L1210/0 and L1210/DDP cells also increased up to cyclohexylamine, and then declined. Four ammine/alicyclic amine analogs were evaluated against L1210/DACH cells, which are cross-resistant to tetraplatin, and the clinically predictive M5076 reticulosarcoma. Although the congeners were ineffective or minimally effective in prolonging the survival time of L1210/DACH-bearing mice (T/C = 111%-134%), 20%-40% cure rate was consistently observed and suggested that the compounds possessed a low inherent ability to circumvent resistance in these tumor cells also. In the solid M5076 model, activity was greatest (tumor growth delays of about 25 days) for the alicyclic homologs containing the ammine/cyclobutylamine or ammine/cyclopentylamine carrier ligand combination. In summary, ammine/amine platinum (II) analogs have demonstrated promise at the preclinical level in their ability to circumvent acquired resistance, which is a major drawback of cisplatin use in treating cancer.
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PMID:Ammine/amine platinum (II) complexes effective in vivo against murine tumors sensitive or resistant to cisplatin and tetraplatin. 792 27

Ammine/amine dichloroplatinum(II) complexes have been evaluated for structure-activity relationship in wild-type L1210/0, 185-fold cisplatin-resistant L1210/DDP and 39-fold tetraplatin-resistant L1210/DACH murine leukemia cells. The mechanism of resistance in these cell lines is multifactorial, with DNA repair playing a dominant role. The amines incorporated in the complexes were selected from the alicyclic, heterocyclic and isoaliphatic class, and contained 3, 4, 5 or 6 carbon atoms. The studies demonstrated that ascending each of the homologous series increased cytotoxic potency against sensitive and cisplatin-resistant cell lines and, more importantly, reduced the cross-resistance of cisplatin-resistant cells. Resistance factors (IC50 in resistant cells/IC50 in wild-type cells) were substantially lower than those for cisplatin, but greater than those seen for tetraplatin. In L1210/DACH cells, the potency remained similar across the alicyclic and isoaliphatic series, while there was a consistent decrease in activity in the heterocyclic series for each stepwise increase in amine size. Furthermore, the relationship between structure and resistance factor in L1210/DACH cells was in direct contrast to that seen in the L1210/DDP model in that the factors increased on ascending the homologous series stepwise. The lower members of the alicyclic and heterocyclic series and cisplatin had comparable resistance factors in the L1210/DACH line; higher members displayed resistance factors that were comparable to or greater than that of tetraplatin. These results provide evidence for amine class and size as factors that can modulate the potency and capacity of ammine/amine platinum complexes to circumvent cisplatin or tetraplatin resistance.
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PMID:Circumvention of platinum resistance: structure-activity relationship for homologous series of ammine/amine platinum(II) complexes in L1210 cell lines. 794 26

Three homologous alicyclic mixed amine cis-(NH3)(R-NH2)Cl2Pt(II) complexes, in which R = C3H5, C6H11, and C8H15 (complexes abbreviated C3, C6, and C8, respectively), were evaluated with reference compounds cisplatin and tetraplatin for antitumor activities and biochemical pharmacology in wild-type (murine leukemia L1210/0 and human ovarian A2780) and corresponding variant cell lines resistant to cisplatin (L1210/DDP and 2780CP) and tetraplatin (L1210/DACH and 2780TP). Cytotoxicities, measured by either a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or a clonogenic assay, were maximal for the C6 complex, which was up to 12-, 40-, and 6-fold more potent than C3 against wild-type, cisplatin-resistant, and tetraplatin-resistant models, respectively, and up to 2-fold more potent than C8 against these cell lines. In general, cross-resistance to mixed amine analogues was partial in cisplatin- and tetraplatin-resistant cells and decreased (in L1210/DDP and 2780CP) or increased (in L1210/DACH and 2780TP) with increase in the alicyclic ring size. The increase in ring size resulted in a corresponding increase in partition coefficient, which correlated directly with intracellular accumulations of mixed amine analogues in all cell lines. However, the intracellular DNA-platinum adducts, and not cellular platinum content, was the pharmacological entity that corresponded closely to potencies of the molecules. DNA adduct formation was disproportionate to the level of cellular drug accumulation. For instance, complex C8, which accumulated to the greatest extent in any given cell line, produced adduct levels that were similar to or lower than those produced by C6. A partial explanation for this observation was the demonstrated reduced rate of binding of C8 to DNA. This study has highlighted the significance of alicyclic ring size in modulating the potency, cross-resistance profile, and biochemical pharmacology of mixed amine platinum(II) complexes in sensitive and cisplatin- or tetraplatin-resistant tumor cells.
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PMID:Biochemical pharmacology of homologous alicyclic mixed amine platinum(II) complexes in sensitive and resistant tumor cell lines. 801 68


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