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)

The biological activity of a series of dinuclear bis(platinum) complexes of formula [(cis-PtX2-(NH3)]2(NH2(CH2)nNH2)] (X = Cl, n = 4-9, compounds 6-11; X2 = malonate, n = 5 or 6, compounds 12 and 13) is described in selected murine leukemia, murine solid tumor, and human tumor cell lines and in murine leukemia cell lines rendered resistant to cisplatin (cis-[Pt(NH3)2Cl2]). The bis(platinum) compounds showed greater activity in vitro against murine tumor cell lines resistant to either cisplatin or DACH ([Pt(DACH)Cl2]). The resistance factor is dependent on chain length of the diamine, and the structural feature of a dinuclear complex is of general use in reducing cross-resistance with cisplatin. In vivo [(cis-PtCl2(NH3)]2(NH2(CH2)5NH2)] (7) showed a % T/C of 204 against murine L1210 leukemia resistant to cisplatin compared to a % T/C of 104 for cisplatin itself at optimal doses. The complex [(Pt(mal)(NH3)]2(NH2(CH2)6NH2)] (13) was highly active in the colon 26 tumor line with 3/10 tumor-free survivors (dose of 186 mg/kg, ip D1,5,9); however, 13 was subject to substantial cross-resistance in the cisplatin resistant L1210 leukemia (% T/C 139 versus % T/C of 223 in the sensitive line). In four selected human tumor lines in vitro, compounds 6-11 were uniformly more potent than cisplatin. In the corresponding xenografts, compound 7 showed greater activity in the HCT-8 (coloadenocarcinoma) and H23 (nonsmall cell lung), but diminished potency in AH125 and H520 (both nonsmall cell lung) lines in comparison to cisplatin. Retention of activity against cisplatin-resistant cell lines and a different spectrum of activity compared to cisplatin in some human tumor cell lines suggest that this class of complexes is mechanistically different from mononuclear complexes and worthy of further development toward clinical trials.
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PMID:Anticancer activity in murine and human tumor cell lines of bis(platinum) complexes incorporating straight-chain aliphatic diamine linker groups. 133 74

Four new sugar:mitomycin C derivatives were synthesized by coupling of N-1 of mitomycin C with tetra-O-acetylglucopyranosyl isothiocyanate and 3,4,6-tri-O-acetyl-2-(N-acetylamino)-2-deoxyglucopyranosyl isothiocyanate. Conversion of each derivative to its water-soluble analogue was achieved by deacetylation, using saturated NH3:CH3OH. Antitumor activity, assessed using the in vivo murine P388 ascitic leukemia system, demonstrated efficacy comparable with the parent mitomycin C. However, unlike the highly myelosuppressive parent drug, optimal antitumor activity is achieved at doses which produce only limited leukopenia.
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PMID:New sugar mitomycin C analogues: preparation, murine P388 antitumor activity, and leukopenia induction. 212 4

A series of new platinum(II) amine complexes containing 1,1- and 1,2-cyclobutanedicarboxylate ligands, cis-[PtA2(1,1-CBDCA)] (A = RNH2, where R = C2H5, n-C3H7, n-C4H9, n-C5H11, n-C6H13, c-C3H5, c-C5H9, c-C6H11; A2 = ethylenediamine, 1,3-diaminopropane), cis-[PtA2(1,2-CBDCA)] (A = NH3, RNH2 where R = CH3, C2H5, n-C3H7, n-C4H9, c-C3H5) and trans-[Pt(NH3)2(1,1-CBDCAH)2] (CBDCA, CBDCAH = dianion and monoanion of the dicarboxylic acid, respectively) have been synthesized by an improved route. These complexes are stable in aqueous solution and show good aqueous solubility. The [Pt(c-C3H5NH2)2(1,1-CBDCA)] can be isolated in white, grey and blue forms. The grey and blue forms exhibit ESR signals analogous to the so-called platinum blues. The existence of the blue form in aqueous solution is time and temperature dependent. Several of the complexes have been tested against leukaemia L1210 in male BDF mice and activity appears to decrease with the increase in length of the aliphatic chain (or increase in size of the alicyclic ring) of the primary amine. The Yoshida lymphoscarcoma screen, usually insensitive to platinum drugs, was found to respond well to [Pt(n-C4H9NH2)2(1,1-CBDCA)] in 5-day subcutaneously implanted tumours in female Wistar rats.
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PMID:Synthesis, characterization and anti-tumour testing of some platinum(II) amine complexes containing 1,1- and 1,2-cyclobutanedicarboxylate ligands. 215 16

A series of platinum complexes of the form cis-M[PtA2(PC)] (I) has been prepared and tested for antitumor activity in mice. Compounds in this series contain either two monodentate amine ligands (A), such as NH3 or isopropylamine, or one bidentate diamine (A2), such as ethylenediamine, 1,2-diaminopropane, or 1,2-diaminocyclohexane. The PC ligand is a bidentate, O-bound, phosphono carboxylate chelate of the form -O2C(CR1R2)nPO3-, where n = 0 or 1 and R1 and R2 are chosen from H, methyl, ethyl, propyl, butyl, phenyl, or pentanoic acid substituents. The resulting complexes (I) were prepared as the free acids (M = H) or as sodium salts (M = Na). Members of this series have demonstrated good activity in a number of tumor screens. A total of 18 platinum-phosphono carboxylate (Pt-PC) complexes were tested against Sarcoma 180 ascites (S180a) in CFW mice, with 13 analogues showing activity above the 50% ILS level. Antitumor activity was also observed vs L1210 leukemia in CDF1 mice, where six of the 12 compounds tested gave ILS values in the 60-160% range, and vs M5076 reticulum cell sarcoma (sc tumor, iv drug), where four of the four compounds tested gave ILS and T-C values comparable to that of cisplatin. Each of the Pt-PC complexes was characterized by NMR (195Pt, 13C, and 31P), HPLC, and elemental analysis. These compounds, which are anionic at neutral pH, display excellent solubility and stability in aqueous media, such as phosphate-buffered saline and fetal calf serum. On the basis of a comparative study of BUN and serum creatinine levels in treated mice, representative complexes from this series are also less kidney toxic than cisplatin. The results of these studies demonstrate that the platinum-phosphono carboxylate complexes are a promising new class of antitumor agents.
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PMID:cis-diamineplatinum (II) complexes containing phosphono carboxylate ligands as antitumor agents. 229 7

The antitumor and DNA-binding properties of a group of oligomeric platinum(II) and platinum(IV) complexes are described. The compounds, having the stoichiometry [cis-PtII(X)2(mu-OH)]2(NO3)2, where X is NH3, NH2CH2CH3, and NH2CH(CH3)2, were found to be inactive or only weakly active against L-1210 leukemia. In vitro studies involving PM2-DNA show that these compounds bind to and unwind closed circular DNA in a manner similar to cis-PtII-(NH3)2Cl2. The Pt(IV) complexes produced by hydrogen peroxide oxidation of the Pt(II) dimers are inactive as antitumor agents and are incapable of unwinding PM2-DNA. The cyclotrimer [cis-PtII(RR-DACH)(mu-OH)]3(NO3)3, where RR-DACH is (R,R)-1,2 diaminocyclohexane, exhibits potent antitumor activity against L-1210 leukemia and modest activities with B-16 and M5076 tumor lines. This compound platinates DNA, causing DNA unwinding and mobility shifts.
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PMID:Antitumor and DNA-binding properties of a group of oligomeric complexes of Pt(II) and Pt(IV). 237 44

A series of 32 cationic platinum(II) complexes of the form cis-[PtA2(Am)Cl]+, where A is a monodentate (NH3 or i-PrNH2) or A2 is a bidentate (ethylenediamine or 1,2-diaminocyclohexane) amine and Am is either a heterocyclic amine based on a pyridine, pyrimidine, purine, piperidine, or a saturated amine (RNH2) ligand, was prepared and screened against in vivo murine tumor models. Each compound was tested against Sarcoma 180 ascites (S180a) in mice, with 20 members of the series showing activity (ILS greater than 50%). Antitumor activity also was demonstrated in 4 of 16 compounds tested in the L1210 murine leukemia model (ILS greater than 25%) and in 3 of 3 tested in the P388 murine leukemia model (ILS greater than 30%). The most active and potent analogues of the series were obtained when A was NH3 and Am was N1-pyridine, N1-4-methylpyridine, N1-4-bromopyridine, N1-4-chloropyridine, N3-cytosine, or N7-2'-deoxyguanosine. Complexes containing chelating and saturated amine ligands (A), as well as two trans isomers of active cis analogues (trans-[Pt(NH3)2(Am)Cl]+, where Am = N1-pyridine or N1-4-methylpyridine), were inactive in the S180a screen. All complexes were characterized by means of elemental analysis, HPLC, and 195Pt NMR spectroscopy, and the structure of one analogue, cis-[Pt(NH3)2(N3-cytosine)Cl](NO3), was determined by using single-crystal X-ray diffraction methods. While members of this series of compounds demonstrate antitumor activity in vivo, these new agents are not classical analogues of cisplatin (i.e. cis-[PtA2X2] complexes), as they contain three nitrogen donors and only one leaving group. The results of these studies suggest that further work should be conducted to better define the limits of the structure-activity relationships among platinum(II) complexes.
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PMID:Chemical and biological properties of a new series of cis-diammineplatinum(II) antitumor agents containing three nitrogen donors: cis-[Pt(NH3)2(N-donor)Cl]+. 290 24

A comparison of the inhibition of DNA synthesis by the two geometrical bidentate isomers cis- and trans-Pt(NH3)2Cl2 and by the monodentate [Pt(dien)Cl]Cl in a model used for screening potential antitumor compounds, the L1210 leukemia cells, is presented. The efficacy of penetration after a 2 hours Pt treatment is in the order trans (8) greater than cis (1) approximately dien (0.7). DNA replication is reduced to 50% of the control when 1.8 X 10(-4), 2.4 X 10(-4) and 80 X 10(-4) Pt atoms were bound per nucleotide for cis, trans and dien derivatives, respectively. If we admit that DNA is the pharmacological target of Pt antitumor compounds, these results suggest that a quantitative inhibition of DNA synthesis is certainly not correlated with antitumor activity.
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PMID:cis-Pt(NH3)2Cl2 and trans-Pt(NH3)2Cl2 inhibit DNA synthesis in cultured L1210 leukemia cells. 668 56

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

A series of C-6-substituted methyl mitomycins was synthesized and evaluated for anticellular and antitumor activities. These novel compounds were prepared by Michael addition of various alcohols or thiols to 6-demethyl-7,7-(ethylenedioxy)-6,7-dihydro-6-methylidenemitosanes followed by treatment with NH3 or MeOH/K2CO3. Most compounds were potent against HeLa S3, and some of them showed superior activity to that of mitomycin C (MMC) against P388 leukemia and sarcoma 180 in mice. In addition, some compounds exhibited remarkable activity against MMC-resistant P388 in mice. FAB-MS spectra of these mitomycin derivatives showed the elimination of the C-6-methyl substituents from the mitomycin skeletons to form quinonemethides. Interestingly, treatment of 6-demethyl-6-[[(2-pyrimidinyl)thio]methyl ]mitomycin C (12v) with diethylamine afforded 6-demethyl-6-[(diethylamino)methyl]mitomycin C (31) in good yield. These results suggested that the C-6-substituted methyl mitomycins would have different biological character from that of MMC.
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PMID:Synthesis and antitumor activity of novel mitomycin derivatives containing functional groups at the C-6-methyl position. 802 18

1,3-Dithiol- and 1,3-dithiolan-2-ylidenemalonatoplatinum(II) complexes A2Pt(OOC)2C = CR2 (A = NH3, cyclopropylamine (CPA) or A2 = ethylenediamine(EDA), trans(+/-)-1,2-diaminocyclohexane(DACH); R2 = -SCH = CHS-, -SCH2CH2S-) have been synthesized and subjected to in vivo assay for antitumor activity after characterization by means of elemental analysis, IR spectroscopy, and x-ray analysis. The molecular structure of (CPA)2Pt(OOC)2C = CSCH = CHS has been determined by x-ray diffraction: space group P2(1)/n, a = 7.955(1), b = 16.912(2), c = 15.116(2) A, beta = 102.74(1) degrees, z = 4, R = 0.032, Rw = 0.035. Among the Pt(II) complexes studied, biscyclopropylamineplatinum(II) complexes both of the above-mentioned dicarboxylate leaving groups exhibited much higher antitumor activity against the leukemia L1210 cell line compared with the known cisplatin.
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PMID:Synthesis, structure, and antitumor activity of 1,3-dithiol- and 1,3-dithiolan-2-ylidenemalonatoplatinum(II) complexes. 817 95


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