Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of preheating EMT6 cells in vitro on their response to cytotoxic agents of either 43 degrees C or 37 degrees C has been investigated. Preheating for 3 h at 40 degrees C produced measurable protection (thermal tolerance) to subsequent treatment for 1 h at 43 degrees C. This preheat treatment was further found to reduce cell killing by BLM and BCNU (drug tolerance) present during 1 h at 43 degrees C. In contrast, no such heat-induced drug tolerance was seen with ADR. An additional effect with ADR was the apparent elimination of heat-induced thermal tolerance at toxic drug doses. However, preheating under these conditions had no effect on the subsequent cytotoxicity of any of these drugs at 37 degrees C. Also, preheating for 1 h at 43 degrees C was found to sensitize cells to BLM and BCNU toxicity at 37 degrees C but to protect against ADR toxicity. The results are discussed in relation to known mechanisms of cell killing by heat and of thermal tolerance.
Br J Cancer 1979 Apr
PMID:The interaction of thermal tolerance with drug cytotoxicity in vitro. 8 13

The important advances made in recent years in the therapy of adult ALL have been reviewed. The definition of bad-prognosis patients has been improved and includes those with T-ALL, ABLL, and Ph1+ALL, in addition to those presenting with evidence of extensive disease. In contrast to childhood ALL, induction chemotherapy should include another drug (or drugs) in addition to VCR and prednisolone, and one of the anthracycline drugs (ADR or DNR) has been employed most frequently in this context. Such therapy should result in a CR rate of 70 to 75%. Similar to the experience in childhood ALL, the improvement in haematological response rate has led to an apparent increase in CNS leukaemia, and the need for adequate CNS prophylaxis is stressed. Despite these improvements, the outlook for adults with ALL is not yet as good as it is for childhood ALL. Controlled studies involving large numbers of patients are urgently needed to provide answers to a number of questions. In induction therapy, the use of higher drug dosage, the use of more and other drugs, and the use of an individual patient's risk factors to determine drug dosage, must be assessed. The benefits of consolidation therapy and the optimal duration and intensity of maintenance therapy have yet to be established. Methods of CNS prophylaxis other than cranial irradiation and IT MTX must be carefully studied. These important questions require that adult patients with ALL should be concentrated in centres capable of providing optimal overall care and, at the same time, able to conduct the necessary clinical trials.
Cancer Treat Rev 1978 Jun
PMID:The management of adult acute lymphoblastic leukaemia. 36 95

The effects of emetine on protein and DNA synthesis in vitro and in vivo were compared in P388 leukemia cells (P388/S) and in an adriamycin-resistant subline of P388 leukemia (P388/ADR), which was completely cross-resistant in vivo to emetine. In P388/ADR cells in vitro no apparent resistance to emetine was found; no difference in cytotoxicity was evident in P388/S or P388/ADR cells exposed to emetine in vitro for 1 or 6 hours. Protein and DNA synthesis was inhibited to a similar extent in P388/S and P388/ADR cells at equivalent concentrations of the drug. However, inhibition of protein synthesis by emetine in P388/ADR cells was more reversible than in P388/S cells when the cells were exposed to emetine and subsequently incubated in drug-free medium for 1 hour prior to addition of labeled L-leucine. Differences between P388/S and P388/ADR cells were evident in vivo. The duration of inhibition (greater than 90%) of protein and DNA synthesis in P388/ADR cells was about 8 hours compared to 24 hours in P388/S cells following administration of a therapeutic dose of 25 mg emetine/kg to tumor-bearing mice. The level of radioactivity in the P388/ADR cells 24 hours after in vivo administration of the emetine analog, (+/-)-[3'-14C]2,3-dehydroemetine, was only 26% of that in P388/S cells. This evidence suggests that the resistance of P388/ADR to emetine is due to decreased retention of the drug.
J Natl Cancer Inst 1978 May
PMID:Biochemical parameters of resistance of an adriamycin-resistant subline of P388 leukemia to emetine, an inhibitor of protein synthesis. 64 26

A subline of P388 leukemia resistant to adriamycin (P388/ADR) was developed by exposure to the drug in vivo. Resistance to adriamycin proved to be a stable characteristic of P388/ADR. There was no significant inhibition of nucleic acid synthesis in P388/ADR cells in vivo following a dose of 10 mg/kg of adriamycin in contrast to a prolonged and complete inhibition, particularly of DNA synthesis, observed in parental sensitive P388 leukemia cells. P388/ADR proved to be completely cross-resistant to a spectrum of anthracycline derivatives. Cross-resistance was observed to nonanthracycline DNA intercalating agents (with the exception of anthramycin), to agents which interfere with mitotic spindle function, and to antineoplastic inhibitors of protein biosynthesis (with the exception of bruceantin). P388/ADR was sensitive to antimetabolites and alkylating agents. Cross-resistance was also observed to several agents (ICRF-159, a terephthalanilide, taxol, lymphosarcin, bouvardin, and a crude extract of Ervatamia hyneana) whose mechanisms of action have not yet been clearly defined. This observation has proved useful in providing a lead for determination of mechanism of action of some of these drugs. The pattern of cross-resistance of a subline of P388 leukemia resistant to daunorubicin, though not studied extensively, appears to be similar to that of P388/ADR.
Cancer Treat Rep 1978 Oct
PMID:In vivo characteristics of resistance and cross-resistance of an adriamycin-resistant subline of P388 leukemia. 70 55

Mechanisms contributing to reduced cytotoxic drug accumulation were studied in two multidrug-resistant (MDR) human lung cancer cell lines without P-glycoprotein expression. In these (non-small cell) SW-1573/2R120 and (small cell) GLC4/ADR MDR cells, the steady-state accumulation of [14C]daunorubicin was 30 and 12%, respectively, of that in the parent cells. When cells, at steady state, were permeabilized with digitonin, the amount of daunorubicin binding increased only in the resistant cells. The reduced accumulation of daunorubicin in the SW-1573/2R120 and GLC4/ADR cells was accompanied by a lower initial (2 min) uptake rate of this drug. No difference in initial efflux rate of daunorubicin from preloaded cells could be detected between sensitive and resistant SW-1573 cells. However, daunorubicin was extruded 5-fold faster from GLC4/ADR cells than from the parental cells. In the presence of the energy metabolism inhibitors sodium azide and deoxyglucose, the reduced daunorubicin accumulations in the SW-1573/2R120 and GLC4/ADR MDR cells were (almost) completely reversed. The effects of these inhibitors on drug uptake were already apparent during the earliest measured time points (less than 15 s). Also, the enhanced efflux of daunorubicin from GLC4/ADR cells was inhibited. In ATP-depleted cells, the intracellular pH was lowered by approximately 0.3 units in resistant as well as in sensitive cells. The lower intracellular pH, however, could not account for the increase in daunorubicin accumulation in the resistant cells. Also, for vincristine and etoposide, the increases in drug accumulation under energy-deprived conditions were more pronounced in the resistant SW-1573/2R120 cells than in the parent SW-1573 cells. These results suggest that accumulation of drugs in the non-P-glycoprotein MDR human lung carcinoma cell lines SW-1573/2R120 and GLC4/ADR is reduced by an energy-dependent drug export mechanism which prevents efficient transport of drug to the target. Since P-glycoprotein expression in lung tumors is generally low, these MDR lung cancer cell lines can be used as a model to study alternative mechanisms leading to multidrug resistance in this tumor type.
Cancer Res 1992 Jan 01
PMID:Energy-dependent processes involved in reduced drug accumulation in multidrug-resistant human lung cancer cell lines without P-glycoprotein expression. 130 22

Carmethizole hydrochloride [1-methyl-2-methylthio-4,5-bis(hydroxymethyl)imidazole-4', 5'-bis(N-methylcarbamate)hydrochloride, NSC 602,668; hereafter called carmethizole] is a new antitumor drug that has shown relatively broad activity in initial evaluations against several murine tumors and human tumor xenografts in vivo. The present studies were designed to address questions about carmethizole's activity against established disease, its activity on different treatment schedules, and the extent of its cross-resistance with established drugs. Human MX-1 mammary carcinoma, human NCI-H82 small-cell lung carcinoma, and human LOX amelanotic melanoma xenografts in athymic mice were used to determine the drug's activity against established disease; the NCI-H82 lung-tumor xenograft in athymic mice was used to explore its schedule dependence; and a series of drug-resistant murine leukemias provided an in vivo cross-resistance profile. When injected i.p., carmethizole exhibited antitumor activity against advanced-stage s.c. MX-1 mammary, s.c. NCI-H82 lung, and i.p. LOX melanoma xenografts and was as effective against established disease (MX-1 and LOX) as it was against early-stage disease (no data are available for early-stage NCI-H82). The therapeutic effect of carmethizole was not route-dependent, as was evidenced by the similar delays observed in tumor growth following i.p. and i.v. administration. The use of a split-dose schedule on a single day instead of one bolus injection yielded an increase in the total dose delivered, resulting in an increased delay in tumor growth. Murine leukemias resistant to vincristine (VCR), amsacrine (AMSA), or methotrexate (MTX) were not cross-resistant to carmethizole. However, murine leukemias resistant to doxorubicin (ADR), melphalan (L-PAM), cisplatin (DDPt), 1-beta-D-ara-binofuranosylcytosine (ara-C), and 5-fluorouracil (5-FU) were cross-resistant to carmethizole, suggesting that patients who have previously been treated with any of these agents might be less likely to respond to carmethizole than those who have had no opportunity to develop resistance to any of these compounds. We anticipate that the information derived from these studies may be useful in the design of clinical trials of carmethizole and may stimulate additional basic research on the mechanism of action of this new agent.
Cancer Chemother Pharmacol 1992
PMID:Antitumor activity and cross-resistance of carmethizole hydrochloride in preclinical models in mice. 132 3

Inhibitors of protein phosphatases 1/2A (okadaic acid and calyculin A) exhibited differential cytotoxicity toward three human leukemia cell lines, in an increasing order of resistance, HL60 less than HL60/ADR less than K562 cells. Cytotoxicity of the toxins was associated with marked mitotic arrest of the cells, characterized by chromatid scattering/overcondensation and abnormal mitotic spindles. In all cases, calyculin A was more potent than okadaic acid. Protein phosphorylation experiments in intact cells revealed that HL60/ADR, the adriamycin-resistant variant, showed a higher overall phosphorylation of nuclear proteins than the drug-sensitive parental HL60, and that phorbol ester (protein kinase C activator) and calyculin A appeared to more specifically stimulate phosphorylation of p66 and p60, respectively. It was suggested that the toxins might be useful in delineating mechanisms underlying certain properties of cancer cells (such as multidrug resistance, mitosis and differentiation) related to protein phosphorylation/dephosphorylation reactions.
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PMID:Comparative effects of protein phosphatase inhibitors (okadaic acid and calyculin A) on human leukemia HL60, HL60/ADR and K562 cells. 132 92

We have investigated the cell kinetic effect of four carcinostatic agents (MMC, CDDP, ADR and 5-FU) on the human gastric cancer cell line (KATO-III; signet ring cell carcinoma) by means of flow cytometry (FCM), using bromodeoxyuridine (BrdU) and its monoclonal antibody. Cancer cells in the S phase were first labelled with BrdU and then the bivariate DNA/BrdU distribution was examined to analyze the effect on the cell cycle. Furthermore, cells were reincubated at 24 hours after labelling to evaluate the cell turnover during FCM. MMC, CDDP and ADR assembled the cells into late S phase and G2M phase, while 5-FU assembled them into S phase. after 24 hours, cells with cessation of cell cycle had inhibited their proliferation. We conclude that this technique can be usefully applied as a susceptibility test of carcinostatic agents, since it could define the phase where carcinostatic agents acted on cancer cells.
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PMID:[Cell kinetic effect of carcinostatic agents using BrdU and its monoclonal antibody]. 133 16

To identify the role of protein kinase C (PKC) isoforms in multidrug resistance in tumor cells, we examined the PKC isoform pattern in the multidrug resistant P388/ADR cell line and studied the effect of down regulation of PKC isoforms on intracellular daunorubicin accumulation and P-glycoprotein expression. Using monoclonal antibodies to PKC alpha, beta and gamma and flow cytometry technique we showed that P388/ADR cells overexpressed PKC alpha and beta as compared to drug sensitive P388 cells. Prolonged treatment of P388/ADR cells with phorbol myristate acetate (PMA), a procedure that is known to down regulate PKC, resulted in the down regulation of total PKC activity and the PKC beta isoform (at the protein level) that was accompanied by the correction of daunorubicin accumulation in P388/ADR cells. The level of expression of P-glycoprotein in PMA treated cells was similar to that of untreated cells. These results suggest that PKC beta regulates the drug efflux function of P-glycoprotein.
Cancer Lett 1992 Feb 14
PMID:Protein kinase C isoforms in multidrug resistant P388/ADR cells: a possible role in daunorubicin transport. 134 51

Multidrug resistance (MDR) in tumor cells is frequently associated with reduced cellular cytostatic drug accumulation, caused by the drug efflux protein, P-glycoprotein (Pgp). The action of Pgp in tumor cells can be detected by measuring the increase of daunorubicin accumulation upon blocking Pgp with drugs such as verapamil. A number of MDR cell lines have been described, characterized by decreased drug accumulation without Pgp being present. For such non-Pgp MDR cells no gene probes or functional assays are available to study this phenotype in clinical tumor specimens. We have worked out a method which enables the detection of drug-transport-related decreases in cellular daunorubicin accumulations without the need for the use of specific Pgp blockers. The cells used were SW-1573-, GLC4- and HT1080-sensitive cell lines, which accumulated (corrected for DNA content) 272%, 1,288% and 203% more daunorubicin than the non-Pgp MDR sublines SW-1573/2R120, GLC4/ADR and HT1080/DR4. When the plasma membranes of these MDR lines were permeabilized with 20 microM digitonin an increase to 282%, 1,260% and 239% of 14C-daunorubicin control accumulation was measured (at pH = 7.35). The intracellular pH measured with BCECF was the same in parent and corresponding MDR cells, excluding the role of pH differences in the measured effects. This method provides a tool allowing the detection of cellular mechanisms (including Pgp) which are related to active outward transport of daunorubicin.
Int J Cancer 1992 Apr 01
PMID:Probing daunorubicin accumulation defects in non-P-glycoprotein expressing multidrug-resistant cell lines using digitonin. 134 41


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