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)

The combined effect of cisplatin (CDDP) with various types of antitumor drugs was examined in P 388 leukemia in vivo. Three representative drugs were chosen from every group of alkylating agents, antitumor antibiotics, antimetabolites, and plant originated drugs. According to their dependency on administration schedules, the dose-dependent and time-dependent drugs were administered once, and daily 5 times, respectively, before and after the single administration of CDDP. In addition to these sequential combinations, simultaneous treatment with CDDP was examined for the drugs which were singly administered. The combined effect was assessed by comparing ILS (increase in life span) in a combined group with the sum of ILS's of each of the 2 single-treatment groups. Synergistic effect was observed in the combination of CDDP with all drugs except MMC. Among them CYC, CQ, ACNU, ADR, PEP, ET, VCR, and VDS produced synergistic effect in any treatment schedules, irrespective of the combination sequences. In the cases of the combination with antimetabolites, the combined effect was depended on the treatment sequences; prior treatment of 5-FU, and posterior treatment of Ara-C and MTX to CDDP administration exhibited a synergistic effect, but the combination in reverse sequence remained almost additive.
 ...
PMID:[Combined effect of CDDP with various types of antitumor drugs against P 388 leukemia]. 273 70

A series of 2-aminoalkyl-5-nitropyrazolo [3,4,5-kl]acridines (pyrazoloacridines) were tested in vitro against a panel of multidrug-resistant cell lines comprising Adriamycin-resistant P388 leukemia, B16 melanoma, and mammary adenocarcinoma 16c. This new class of anticancer agents, particularly the 9-substituted methoxy derivatives, exhibited significant activity against all of the lines tested. The degree of cross-resistance to these compounds ranged from zero to 8-fold in the 138-fold Adriamycin-resistant P388/ADR line and was greatly diminished in the B16/ADR and 16c/ADR lines. Selected pyrazoloacridines were subsequently tested in vivo against B16 and B16/ADR cells established as solid tumors from the tissue culture line and shown to retain a significant degree of Adriamycin resistance. Whereas the B16/ADR line exhibited 2 logs less net tumor-cell kill than the B16 parent in response to Adriamycin treatment, the resistant tumor was completely sensitive to the pyrazoloacridines tested and proved in some experiments to be collaterally sensitive. The favorable activity of the pyrazoloacridines against these Adriamycin-resistant tumor lines points to the potential efficacy of these compounds against multidrug-resistant tumors encountered clinically.
 ...
PMID:Activity of the pyrazoloacridines against multidrug-resistant tumor cells. 275 1

Cultured murine leukemia P388 cell populations were derived from P388 cells resistant to vincristine (P388/VCR), adriamycin (P388/ADR), and 1-beta-D-arabinofuranosylcytosine (P388/ARA-C) that were developed in vivo and to the parental drug-sensitive cells (P388/O) that were passaged in vivo. The doubling times of the cultured cell populations (mean +/- SD) between cell densities of 5 x 10(4) and 1 x 10(6) cells/ml were 14.2 +/- 2 h (P388/O), 16.5 +/- 1.9 h (P388/VCR), 16.9 +/- 1.2 h (P388/ADR), and 15.0 +/- 1.4 h (P388/ARA-C). Exponentially proliferating cultured cell populations were exposed to selected homoharringtonine (HHT) concentrations for 24 h and the surviving cell fractions were determined by colony formation in semisolid medium. The results, based on differential sensitivity of the cell populations to HHT, indicated that cultured P388/VCR cells were cross-resistant to 0.018-1.8 micrograms/ml HHT, P388/ADR cells were cross-resistant to 0.058-1.8 micrograms/ml HHT, and P388/ARA-C cells were collaterally sensitive to 0.09-0.36 micrograms/ml HHT. The results with the cultured P388/VCR, P388/ADR, P388/ARA-C, and P388/O cell populations were confirmed in animal experiments. CD2F1 mice bearing intraperitoneal (i.p.) implants of 1 x 10(6) P388/VCR, P388/ADR, P388/ARA-C, or P388/O leukemia cells were given HHT i.p. qd on days 1-9 postimplantation. Optimal treatment (less than or equal to LD10) produced in vivo cell kills of 2 to 3 log10 units in P388/O and about 7 log10 units in P388/ARA-C, whereas P388/VCR and P388/ADR cells actually increased by 1-2 log10 units during treatment. The results of this study indicate that cross-resistance (P388/VCR and P388/ADR) or collateral sensitivity to HHT (P388/ARA-C) is a function of the cellular properties of the target tumor cell populations that is independent of host factors.
 ...
PMID:Effect of homoharringtonine on the viability of murine leukemia P388 cells resistant to either adriamycin, vincristine, or 1-beta-D-arabinofuranosylcytosine. 292 72

Mice bearing the P388/S or P388/ADR (doxorubicin-resistant) leukemia were treated with menogaril or mitoxantrone. Both drugs were highly effective against P388/S but were ineffective against the doxorubicin-resistant subline, indicating cross-resistance. These observations may be of use in the design of clinical trials with these drugs.
 ...
PMID:Cross-resistance of menogaril and mitoxantrone in a subline of P388 leukemia resistant to doxorubicin. 294 40

The mechanisms of acquired resistance to MTX were studied in P388 murine leukemia cell lines that were sensitive or resistant to ADR. The rate of MTX accumulation in ADR-sensitive cells that have acquired resistance to MTX was found to be lower than that measured in cells that were sensitive to both drugs. Furthermore, in contrast to drug-sensitive cells, in the ADR-sensitive MTX-resistant cells, most of the intracellular MTX (86.2%) was bound and MTX polyglutamation was not detected. The initial rate of MTX accumulation in cells that were resistant to both drugs was comparable to that measured in cells that were sensitive to both drugs or that were resistant only to ADR. However, in the cells that were resistant to both drugs, the rate of MTX accumulation was maintained at its initial level for a period that was considerably longer than that found in the other cell lines. After 3 h of exposure to MTX, the accumulation of MTX in cells that were resistant to both drugs was fourfold higher than that measured in cells that were sensitive to both drugs. Furthermore, while 65 to 70% of the intracellular MTX was free, in cells sensitive to both drugs, or resistant only to ADR, the corresponding value in cells that were resistant to both drugs was less than 1.5%, and a much lower proportion of the MTX was polyglutamated. The sensitivity to TMQ of ADR-sensitive, MTX-resistant cells was similar to that found in cells that were sensitive to ADR and MTX. However, ADR-resistant cells, sensitive or resistant to MTX, were markedly resistant to TMQ. The sensitivity of ADR-resistant MTX-sensitive cells to TMQ was restored by the presence of 10 microM verapamil. Such an effect was not observed in cells resistant to both drugs. It is suggested that P388 cells that have previously acquired resistance to ADR, when now selected by MTX, retain the MTX-transport system (in contrast to ADR-sensitive, MTX-resistant cells) and become resistant to MTX by increasing the activity of DHFR. The results obtained in ADR-resistant cells also suggested that resistance to TMQ was part of the multidrug resistance phenomenon.
 ...
PMID:Mechanism of acquired resistance to methotrexate in P388 murine leukemia cells and in their doxorubicin-resistant subline. 297 48

Two new classes of actinomycin D analogues, tetracyclic "reverse" analogues and a tricyclic "symmetrical" analogue of actinomycin D, are reported. These analogues bind to DNA and the binding does not occur by an intercalation mechanism. The analogues inhibit the synthesis of DNA and RNA in P388 tumor cells and the growth of CCRF-CEM cells in vitro at nanomolar concentrations. The tetracyclic "reverse" analogues, which are structurally related to the previously reported actinomycin D oxazolyl analogues, are metabolized in the presence of rat hepatic microsomes and tumor cell homogenates. The metabolism takes place with the loss of the oxazole ring; thus the "reverse" analogues produce a major metabolite which is the "symmetrical" analogue; the actinomycin oxazolyl analogues generate 7-hydroxyactinomycin D. Further, the microsomes activate the analogues to free-radical states which catalyze the production of superoxide as shown by stimulation of epinephrine oxidation and also indicated by electron paramagnetic resonance studies. The "symmetrical" and "reverse" analogues also demonstrate very high activities in these systems. In in vivo studies using P388/S, P388/ADR leukemia, and B16 melanoma in mice, the analogues showed increased activity and superior therapeutic index values, in comparison to actinomycin D.
 ...
PMID:"Reverse" and "symmetrical" analogues of actinomycin D: metabolic activation and in vitro and in vivo tumor growth inhibitory activities. 298 84

Diaziquone (AZQ) is a quinone-containing alkylating agent undergoing trials as an antitumor drug. The quinone moiety of this compound places it among a group of compounds whose activity is believed to be modulated by a redox cycle that activates the compounds to their free radicals (e.g., adriamycin). AZQ is unique among these compounds in that it can be reduced to its free radical (AZQH) by a variety of cells in culture, including human and murine cancer cells. Red blood cells (RBC) were also observed to reduce AZQ to its free radical. Using electron spin resonance (ESR), we observed that soon after the AZQ free radical appeared, it decayed and was replaced by a doublet with ESR parameters that suggested the presence of the ascorbyl radical (AH). The identity of AH was confirmed by adding exogenous ascorbic acid to AZQ free radicals generated by a suspension of L1210 murine leukemia cells. The endogenous ascorbic acid was shown to arise mostly from the "buffy coat" of an RBC preparation which contained leukocytes. Leukocytes are second only to the adrenals in level of ascorbic acid in humans. Cyclic voltammetry of ascorbic acid, AZQ, and adriamycin in Hank's Balanced Salt Solution (HBSS pH 7.5), the buffer used for biological measurements, showed that the oxidation peak potential for ascorbic acid (Eap = +0.43 V) is closer to the reduction peak potential for AZQ (Ecp = -0.36 V) than that for adriamycin (Ecp = -0.67 V). This may explain why the ascorbic acid redox system interacts with that of AZQ but not with that of ADR.
 ...
PMID:The influence of ascorbic acid on the free-radical metabolism of xenobiotics: the example of diaziquone. 306 33

Multidrug resistance in cancer chemotherapy occurs when cells develop resistance towards structurally and functionally unrelated drugs. It is speculated that alteration of some fundamental process(es) in the cells leads to the development of multidrug resistance. The sodium pump activity of murine leukemia cell lines P388/S (sensitive) and P388/ADR (resistant) was measured and found to be different in the two cell lines. The rate of sodium pumping, i.e., the ouabain-sensitive rubidium uptake, was consistently lower in the resistant cells compared to their parental controls. Uptake of adriamycin was lower in the resistant cells. Depolarizing the cells with potassium chloride or by inhibiting the pump with ouabain increased the adriamycin uptake in the sensitive cells but not in the resistant cells. Adriamycin did not have any acute effects on the sodium pump activity. It is concluded that the development of drug resistance in cell line P388 is associated with a decrease in sodium pump activity and a lack of depolarization-induced adriamycin uptake; these processes may be causally linked via alterations in cytosolic calcium concentration.
 ...
PMID:Membrane transport changes in an adriamycin-resistant murine leukemia cell line and in its sensitive parental cell line. 334 61

A series of derivatives of 9-anilinoacridine related to the anti-leukaemia agent amsacrine have been tested in continuous exposure growth inhibition assays to determine the degree of cross-resistance in the Adriamycin-resistant P/ADR murine leukaemia line. Measured IC50 values for the two cell lines were only poorly correlated (r = 0.51), and cross-resistance as measured by the ratio of IC50 values varied from 2-fold and 272-fold. A high degree of resistance was found to be associated with the presence of amino or substituted amino groups on the acridine ring system. Logarithmic IC50 values were determined for other cell lines (L1210 leukaemia, Lewis lung carcinoma and HCT-8 human colon carcinoma) and were compared with those for the P388 lines to determine the degree of linear correlation. HCT-8 values were strongly correlated with P/ADR values (r = 0.84) while L1210 values correlated strongly with those of the sensitive P388 line (r = 0.98). Values for Lewis lung cells showed an intermediate pattern and correlated with a linear combination of values for both P388 lines (r = 0.88). Examination of available IC50 values for a number of rodent and human cell lines indicates that their sensitivity patterns are either P388-like or else intermediate between P388 and P/ADR. The series of amsacrine derivatives may be useful in characterizing the nature and degree of multidrug-resistance in cultured cell lines.
 ...
PMID:Relationship between the structure of analogues of amsacrine and their degree of cross-resistance to adriamycin-resistant P388 leukaemia cells. 335 8

The effect of glutathione depletion on cytotoxicity of the anthracycline daunorubicin, and of a copper:bis-thiosemicarbazone chelate, was examined in the P388 murine leukemia and its anthracycline-resistant subline, P388/ADR. Depletion of intracellular glutathione was accomplished through exposure to buthionine sulfoximine, a specific inhibitor of glutathione synthesis. Cytotoxicity of daunorubicin was not altered by glutathione depletion, while responsiveness to the bis-thiosemicarbazone chelate was thereby enhanced.
 ...
PMID:Intracellular glutathione as a determinant of responsiveness to antitumor drugs. 346 80


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>