UMLS:C0023418 - FACTA Search

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Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The earliest reports on the therapeutic use of metals or metal-containing compounds in cancer and leukemia date from the sixteenth and nineteenth centuries. They were forgotten until the 1960s, when the anti-tumour activity of the inorganic complex cis-diammine-dichloroplatinum(II) (cisplatin) was discovered. This led to the development of other types of non-organic cytostatic drugs. Cisplatin has developed into one of the most frequently used and most effective cytostatic drugs for the treatment of solid carcinomas. Numerous other metal compounds containing platinum, other platinum metals, and even non-platinum metals were then shown to be effective against tumours in man and experimental tumours in animals. These compounds comprise main-group metallic compounds of gallium, germanium, tin, and bismuth, early-transition metal complexes of titanium, vanadium, niobium, molybdenum, and rhenium, and late-transition metal complexes of ruthenium, rhodium, iridium, platinum, copper, and gold. Several platnium complexes and four non-platnium-metal antitumour agents have so far entered early clinical trials. Gallium trinitrate and spirogermanium have already passed phase II clinical studies and have shown limited cytostatic activity against certain human carcinomas and lymphomas. The two early-transition metal complexes budotitane and titanocene dichloride have just reached the end of phase I clinical trials and have been found to have an unusual pattern of organ toxicity in man. Titanocene dichloride will soon enter phase II clinical studies.
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PMID:Complexes of metals other than platinum as antitumour agents. 798 18

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

We have examined the relationship between cis-diamminedichloroplatinum(II) (cisplatin) resistance and replicative bypass in the human ovarian carcinoma cell lines 2008, A2780, and their respective cisplatin-resistant derivatives C13* and A2780/DDP. Replicative bypass is defined as the ability of a replication complex to proceed past a DNA adduct known to block or stall the complex during synthesis. Previous studies in our laboratory have shown a 3-4-fold increase in the replicative bypass of platinum-DNA adducts in platinum-resistant murine leukemia cell lines [G. R. Gibbons et al, Carcinogenesis (Lond.), 12: 2253-2257, 1991]. To test for this effect in the human lines, we used a steady-state replication assay which measures the inhibition of DNA chain elongation (based on the incorporation of [3H]thymidine into nascent DNA strands) as a function of the number of platinum-DNA adducts present on the DNA following cisplatin treatment. With this technique we demonstrated a 4.5-fold increase in the replicative bypass ability of the C13* line compared to the 2008 line and a 2.3-fold increase in the bypass ability of the A2780/DDP line compared to the A2780 line. To confirm these results, we performed a pulse-chase replication assay on the 2008 and C13* lines. This assay differs from the first in that DNA chain elongation is measured in a time-dependent manner. With the pulse-chase assay we observed a 4.8-fold increase in the replicative bypass ability of the C13* line compared to the 2008 line. We then examined the specificity of this enhanced bypass by repeating the steady-state assay with the 2008 and C13* lines using as damaging agents 1,2-diaminocyclohexanedichloroplatinum(II), UV radiation (producing pyrimidine dimers), and benzo(a)pyrene-7,8-diol-9,10-epoxide. In both cell lines, 1,2-diaminocyclohexanedichloroplatinum(II)-DNA adducts caused a greater inhibition of DNA chain elongation than cisplatin-DNA adducts. The level of enhanced bypass of 1,2-diaminocyclohexanedichloroplatinum(II)-DNA adducts in the resistant line was 2.1-fold (approximately 2-fold less than the level of enhanced bypass observed with cisplatin-DNA adducts). There was no evidence of enhanced bypass in the resistant line when cells were treated with UV light or benzo(a)pyrene-7,8-diol-9,10-epoxide. These results indicate that the bypass response in the C13* line has some degree of specificity for cisplatin adducts. The specificity of bypass in these cell lines coincided well with the specificity of resistance to each agent.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Enhanced replicative bypass of platinum-DNA adducts in cisplatin-resistant human ovarian carcinoma cell lines. 801 73

A platinum(II) and 3 platinum(IV) ammine/cycloalkylamine homologous series were evaluated for cytotoxicity and biochemical pharmacology in murine leukemia L1210/0, cis-diamminedichloroplatinum(II)- resistant L1210/DDP, and diaminocyclohexaneplatinum-resistant L1210/1,2-diaminocyclohexane (DACH) cells. Within each series, which contained 4 homologues with differing alicyclic (cycloalkyl) ring size (cyclopropane, cyclobutane, cyclopentane, or cyclohexane), cytotoxicity increased with increasing ring size. This appeared to be due to an increase in partition coefficient, and the resulting increase in drug accumulation and intracellular DNA adducts in ascending each of the series. There were exceptions to this generalization, predominantly in L1210/DACH cells, where the biochemical pharmacology was not entirely consistent with the cytotoxic response and suggested that other factors may be at play. The relationship between structure and ability to circumvent cis-diamminedichloroplatinum(II) and/or trans-1R,2R-1S,2S- diaminocyclohexanetetrachloroplatinum(IV) resistance was complex. Ascending the platinum(II) series caused resistance factors to decrease in L1210/DDP cells but increase in L1210/DACH cells. An increase in resistance factors was also observed in ascending the axial chloroplatinum(IV) series in the L1210/DACH line. In contrast, ascending the axial chloroplatinum(IV) series in the L1210/DDP line and axial acetatoplatinum(IV) and axial hydroxoplatinum(IV) series in both cell lines resulted in increases in resistance factors for the first stepwise increase in the cycloalkylamine ring size, but resistance factors then decreased progressively with further increases in ring size. Reduction of the platinum(IV) analogues to the platinum(II) congener appears to be necessary for binding to DNA. The similarity in biological actions between the platinum(II) and axial chloroplatinum(IV) series is likely due to the rapid reduction of tetravalent members to platinum(II) forms. The axial acetatoplatinum(IV) and axial hydroxoplatinum(IV) complexes were reduced more slowly, which may explain their lower potency, but not the ability of the higher member to circumvent both cis-diamminedichloroplatinum(II) and trans-1R,2R-1S,2S- diaminocyclohexanetetrachloroplatinum(IV) resistances. Explanation for this will require additional studies. The results have demonstrated high dependencies on ring size of the carrier amine ligand, valence state of platinum, and the nature of the axial ligand for modulation of potency, cross-resistance property, and biochemical pharmacology of ammine/cycloalkylamine complexes.
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PMID:Axial ligands and alicyclic ring size modulate the activity and biochemical pharmacology of ammine/cycloalkylamine-platinum(IV) complexes in tumor cells resistant to cis-diamminedichloroplatinum(II) or trans-1R,2R-1S,2S-diaminocyclohexanetetrachloroplatinum(IV). 806 66

The synthesis, characterization, and antitumor activity of a series of platinum(IV) complexes of the type DACH-PtIV(X)2Y (where DACH = trans-dl, or trans-l-1,2-diaminocyclohexane, X = OH or Cl, and Y = oxalato, malonato, methylmalonato, tartronato, ketomalonato, 1,1-cyclopropanedicarboxylato, or 1,1-cyclobutanedicarboxylato, are described. These complexes have been characterized by elemental analysis, HPLC, and infrared and 195Pt NMR spectroscopic techniques. The complexes had good in vitro cytotoxic activity (IC50 = 0.14-7.6 micrograms/ml) and were highly active in vivo against leukemia L1210 cells (%T/C = 152- > 600, cisplatin = 218). In addition, excellent in vivo antitumor activities against B16 melanoma (%T/C = 309), M5076 reticulosarcoma (100% cures) and cisplatin-resistant L1210/DDP (%T/C = 217) cell lines were also exhibited by an analog selected for further evaluation.
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PMID:Synthesis and antitumor activity of 1,2-diaminocyclohexane platinum(IV) complexes. 815 10

Acquired drug resistance is a major drawback of using cisplatin in the treatment of cancer; however, platinum 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 previously established that the R,R form of DACH-Pt(II) complex is in general superior. Here, we have examined if specific axial and/or equatorial ligands attached to a platinum(IV) center can modulate the antitumor activities of R,R-DACH-Pt complexes in murine tumor models in vivo. Four series of R,R-DACH-Pt complexes were synthesized, with each series consisting of one platinum(II) complex and three corresponding platinum(IV) analogs, each differing by the chemical nature of the axial ligand (chloro, hydroxo or acetato). Combination of axial chloro with equatorial chloro (Cl2Cl2), 1,1-cyclobutanedicarboxylato (Cl2CBDCA), tartronato (Cl2Tart) or methylmalonato (Cl2MeMal) gave activities which were similar to or greater than those of the corresponding platinum(II) complex in the cisplatin-sensitive L1210/0 or cisplatin-resistant L1210/DDP leukemia and solid M5076 reticulosarcoma models. The exception was the complex Cl2Cl2 in the M5076 model, which was 2-fold less sensitive to this platinum(IV) complex than to the corresponding platinum(II) analog. Axial hydroxo or acetato platinum(IV) complexes were effective in combination with equatorial chloro ([OH]2Cl2 or Ac2Cl2) or tartronato ([OH]2Tart or Ac2Tart) against L1210/0, L1210/DDP and M5076 cells, but effective only against M5076 cells when combined with equatorial 1,1-cyclobutanedicarboxylato (CBDCA) or methylmalonato. The results demonstrated a profound effect of axial and equatorial ligands on the antitumor activities of R,R-DACH-Pt(IV) complexes. Furthermore, these modulatory effects could be influenced strongly by the tumor model. The interesting finding from this structure-activity study was the emergence of R,R-DACH([OH]2Cl2)Pt(IV) complex as a 'lead' analog worthy of further exploration.
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PMID:Modulatory effect of axial and equatorial ligands on antitumor activities of trans-1R,2R-diaminocyclohexane platinum(IV) complexes. 816 29

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