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)

Four polymer bound Pt-complexes have been tested in in vivo and in in vitro systems. No substantial difference in effectivity against P388 leukemia in vivo was found when free trans-1,2-diaminocyclohexaneplatinum(II)-4-carboxyphtalate (TMA) was compared with the polymer bound complexes. The compound with the highest ID50 value in soft agar assay exhibited low effectivity in in vivo testing. Polymer bound Pt-complexes with faster release of the active molecule exhibited in in vivo and in soft agar assay slightly lower activity, when compared with suspension culture test system. Cross resistance of polymer bound complexes was investigated on three cell lines with induced drug resistance against different Pt-complexes. Cross resistance was found between TMA (free and polymer bound) and trans-1,2-diaminocyclohexaneplatinum(II)citrate (PEX) as well as trans-1,2-diaminocyclohexaneplatinum(II)glucarate (PTU) but there was no cross resistance between TMA and cis-diamminedichloroplatinum(II) (cis-DDP).
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PMID:Antitumor activity of four polymer bound trans-1,2-diaminocyclohexaneplatinum(II)-4-carboxyphtalate complexes tested in different model systems. 380 21

As an experimental model for resistance to cis-diamminedichloroplatinum(II) (cis-DDP), murine leukemia L1210 cells have been exposed to a stepwise increase in cis-DDP concentration to produce a variety of resistant cell lines. Intraspecies hybrids of the sensitive and resistant cells were made to determine whether cis-DDP resistance is a dominant or recessive trait. Hybrid cells displayed a partial degree of resistance as compared to the parental cells. To determine whether this was due to a single codominant trait or contribution from a variety of resistance mechanisms, the cells and hybrids were investigated for alterations in the accumulation of drug, as well as alterations in glutathione levels which might inactivate the drug. The cis-DDP-resistant cells demonstrated both a 50% reduction in accumulation of drug and a 1.7-fold increase in intracellular glutathione. Reducing the glutathione levels in these cells with buthionine sulfoximine did not sensitize them to cis-DDP. The hybrid cells had the same accumulation and the same levels of glutathione as the cis-DDP-sensitive cells. Parallel studies were performed with cells resistant to 1,2-diaminocyclohexaneplatinum(II) analogues. These cells also demonstrated reduced drug accumulation but no increase in glutathione. Therefore, both a decrease in accumulation and increase in glutathione may mediate resistance. Both mechanisms represent recessive traits as demonstrated in the cell hybrids. These mechanisms can only account for a small part of the resistance in these cells. A major, dominant mechanism occurs after the DNA has been platinated, but it remains to be determined whether this involves DNA repair, postreplication repair, or some other as yet unidentified process.
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PMID:Multiple mechanisms of resistance to cis-diamminedichloroplatinum(II) in murine leukemia L1210 cells. 382 95

Dichloro-1,2-diaminocyclohexane (DACH):platinum(II), the prototype DACH:platinum complex, had good antitumor activity, was not cross-resistant with cis-dichlorodiammineplatinum(II) (DDP), but was, unfortunately, virtually insoluble in water and was, therefore, not evaluated clinically. This paper summarizes some of the chemical and biological attributes of a series of cis-bisascorbato-DACH:platinum(II) complexes (DAP). Although the primary emphasis has been placed on the DAP complex consisting of the isomeric mixture DACH, a series of complexes using the isomers of either DACH or ascorbic acid have also been synthesized. The synthetic procedure entailed reacting the water-soluble sulfato-DACH:platinum(II) with barium ascorbate, and the water-soluble product DAP was removed from the BaSO4 precipitate by filtration. Based upon elemental analysis, all the complexes had stoichiometric composition of one DACH:one platinum and two ascorbate monoanions. High-pressure liquid chromatography of cis-bisascorbato (mixed-isomer DACH):platinum revealed a series of platinum-containing, ultraviolet-absorbing peaks. All the DAP complexes had significant in vitro cytotoxicity against L1210 leukemia cells (L1210/0) with 50%-inhibitory dose values ranging from 2 to 5 micrograms/ml. None of the complexes was cross-resistant with DDP when tested in vitro against L1210 cells 50-fold resistant to DDP (L1210/DDP). The cis-bisascorbato (mixed-isomer DACH):platinum (DAP-1) was administered i.p. to C57BL X DBA/2 F1 mice inoculated i.p. with 10(6) L1210/0 cells. When administered on Days 1, 5, and 9, the DAP-1 complex consistently produced treated:control values in excess of 200% with several long-term survivors (alive 60 days after tumor inoculation). Further, the DAP-1 complex was totally non-cross-resistant with DDP when tested in vivo against a DDP-resistant L1210 line. Toxicological investigations revealed that DAP-1 was relatively nonnephrotoxic but did cause the expected bone marrow and gastrointestinal toxicity. In summary, the DAP complexes are highly water-soluble, nonnephrotoxic platinum complexes with sufficient antitumor activity to warrant further pharmacological, biochemical, and chemical investigations.
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PMID:Ascorbato(1,2-diaminocyclohexane):platinum(II) complexes, a new series of water-soluble antitumor drugs. 404 Aug 6

A group of Pt-complexes was tested in various in vitro and in vivo systems. Murine P388 leukemia for the in vivo testing and three sublines of L1210 leukemia for the in vitro testing of two 1,2-diaminocyclohexane (DACH) derivatives of platinum were used. The effectivity of DACH-Pt(II) citrate and DACH-Pt(II) isocitrate with different ratio of trans- and/or cis-DACH was compared on the sensitive strain of L1210 and two resistant sublines: L1210 resistant to cis-diammine-dichloroplatinum(II) (cis-DDP) and L1210 resistant to trans-DACH-Pt(II) citrate. No cross-resistance was found between the DACH derivatives and cis-DDP. Slightly higher activity of citrate and trans-DACH in comparison with isocitrate and cis-DACH was found both in suspension culture and in vivo testing.
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PMID:Comparison of the effectivity of two diaminocyclohexane Pt-complexes. 406 88

CDF1 mice were implanted with 10(6) P388 leukemia cells. One day postimplantation, when interferon (IFN) therapy was begun, the tumor burden was ca. 4.8 X 10(6) cells. Therapy consisted of nine consecutive daily intraperitoneal (i.p.) injections of 10(6) units of Ehrlich ascites tumor cell IFN (specific activity 5 X 10(7) IU/mg). The median life span for control animals was 10.0 days versus 18.5 days for the treated animals. It was estimated that about 2 X 10(6) viable P388 cells were present on Day 9 when therapy was discontinued. There was no evidence of toxicity in animals receiving 10(6) units of IFN/day for nine consecutive days. In a separate experiment, control animals challenged as above had a median life span of 9.5 days of versus 15 days for animals receiving 10(6) units of IFN qd on Days 2-10. A third group of animals receiving a single injection of cis-DDP on Day 1 had a median survival of 18.5 days, while a fourth group receiving both cis-DDP on Day 1 and subsequent treatment with IFN survived 26 days. The results are discussed in terms of impact on tumor cell population.
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PMID:Interferon and cis-DDP: combination chemotherapy for P388 leukemia in CDF1 mice. 618 80

The following platinum complexes have been tested: cis-DDP--cis-diamminedichloroplatinum(II), Platinex--1,2-diaminocyclohexaneplatinum(II)citrate, Platuran--1,2-diaminocyclohexaneplatinum(II)-glucarate , TMA--1,2-diaminocyclohexaneplatinum(II)-4-carboxyphthalate,o xo-PT--cis-diamminedichloro-trans-dihydroxyplatinum(IV), CHIP--cis-dichloro-bis-(isopropylamine)-trans-dihydroxyplatinum(IV ), CBDCA--cis-diammine-cyclobutane-1,1-dicarboxylatoplatinum(II ). The activity of all tested complexes againt L1210 cells was higher in soft agar colony assay when compared with suspension culture of the same target cells. Using various doses and schedules oxo-Pt, CBDCA and cis-DDP exhibited the highest in vivo activity against P388 leukemia.
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PMID:In vivo and in vitro effectivity of some platinum complexes. 639 26

The effect of thymidine (TdR) on the preclinical toxicity of cis-diamminedichloroplatinum (II) (DDP) was investigated in the BDF1 mouse and the Sprague-Dawley rat. The effect of TdR on the antitumor activity of DDP was investigated using the ascites P388 murine leukemia model. TdR at 500 mg/kg consistently decreased the recovery of body weight after DDP treatment IP, but did not affect the lethal toxicity of DDP to non-tumor-bearing mice or those with the P388 murine leukemia. This effect was greatest when TdR was injected 30 min prior to DDP and at higher doses of DDP. A 500-mg/kg dose of TdR did not affect the antitumor activity of DDP 5 mg/kg administered on days 1, 5, and 9. Treatment of rats with TdR 500 mg/kg according to various schedules of timing relative to a 5-mg/kg dose of DDP did not consistently affect the DDP-related loss in body weight or nephrotoxicity at day 3. Pretreatment of mice with TdR 1,500 mg/kg 30 min prior to DDP 5 mg/kg (every 4 days X 3) resulted in a slower recovery of body weight, which became more pronounced with increasing doses of DDP. Pretreatment of ascites P388-bearing mice with TdR 1,500 mg/kg increased the number of early deaths when mice were treated with DDP 5 mg/kg (days 1, 5, and 9). These data suggest that the cytotoxicity of DDP is increased by TdR only at higher doses of either drug, but that the antitumor activity against P388 murine leukemia is not affected.
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PMID:Effect of thymidine on the toxicity and antitumor activity of cis-diamminedichloroplatinum (II). 653 57

The synergistic cytotoxic activity exhibited by bifunctional alkylating agents in the presence of methylxanthines has been associated with methylxanthine-induced reversal of alkylator-induced DNA replicon initiation inhibition. This has also been seen with methylxanthines and ionizing irradiation. Methylxanthines do not appear exacerbate drug or ionizing radiation-induced damage. We report here a situation in which methylxanthine-induced reversal of DNA replicon initiation inhibition is not associated with increased cytotoxicity of the alkylator. Murine L1210 leukemia cells were assayed for cytotoxicity following treatment with either L-PAM or cis-DDP in the presence or absence of theophylline. Theophylline increased the cytotoxicity seen after L-PAM treatment but failed to increase the cis-DDP induced cytotoxicity. Analysis of pulse-labeled DNA on alkaline sucrose gradients revealed the expected decrease in DNA replicon initiation in L1210 cells treated with either L-PAM or cis-DDP. Theophylline had no effect on replicon initiation in untreated cells. Theophylline reversed the replicon initiation inhibition in cells treated with either L-PAM or cis-DDP. The reason for the apparent lack of added toxicity of the replicon initiation inhibition reversal in L1210 cells treated with theophylline and DDP is unknown.
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PMID:Theophylline reversal of alkylator-induced replicon initiation inhibition: no correlation with DDP-induced cytotoxicity. 654 56

In vitro drug resistance was induced against cis-diamminedichloroplatinum(II) (cis-DDP), 1,2-diaminocyclohexaneplatinum-(II)citrate (PEX) and 1,2-diaminocyclohexaneplatinum(II)glucarate (PTU) in L1210 leukemia cell line. Using the resistant sublines cross-resistance was found between cis-DDP and cis-diamminecyclobutane-1,1-dicarboxylatoplatinum(II) (CBDCA) and between the three 1,2-diaminocyclohexane (DACH) derivatives tested. No (or low degree) cross-resistance was found between cis-DDP and DACH derivatives.
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PMID:Drug resistance induction and cross-resistance studies with Pt-complexes. 654 68

Pretreatment of Swiss mice and Sprague-Dawley rats with glutathione (GSH) reduced the acute lethal toxicity of cis-dichlorodiammine platinum (II) (cis-DDP) in a dose-dependent manner. The protection was accompanied by reduction of both body weight loss and by reduction of nephrotoxicity, as measured by a rise in serum blood urea nitrogen (BUN), creatinine levels and by histopathologic changes, which occurred 4 days following cis-DDP treatment. The antitumor effects of cis-DDP on experimental tumor models (P388 and Gross leukemia) were not significantly altered by GSH treatment. It is suggested that the partial protection by GSH from acute toxicity of the antitumor drug is directly related to protection of renal function.
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PMID:Protective effect of reduced glutathione against cis-dichlorodiammine platinum (II)-induced nephrotoxicity and lethal toxicity. 668 12


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