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)

Verapamil, a calcium channel blocker, was studied for its effects on the cellular daunorubicin (DNR) accumulation in blast cells and on the sensitivity of the blast progenitors to DNR in 30 acute myelogenous leukaemia (AML) patients. Using flow cytometry, verapamil was shown to increase the accumulation of DNR in blast cells. The effect was more prominent in the patients who showed poorer response to chemotherapy including DNR. The per cent increases of DNR content by verapamil were 6.4 +/- 6.3% and 19.5 +/- 23.1% in the 16 responders and the 14 nonresponders, respectively (P less than 0.05). The data suggest the presence of enhanced efflux of DNR in nonresponders. Marked variation in the effects of verapamil among nonresponders suggests the heterogeneity of the mechanisms of drug resistance involved. Verapamil also enhanced the sensitivity of blast progenitors to DNR. The degree of increase of cellular DNR accumulation by verapamil correlated with the degree of increase in chemosensitivity of blast progenitors (nonresponders, P less than 0.005; responders, P less than 0.05). We conclude that enhanced efflux of DNR in blast progenitors may be related to remission induction failure in at least some of resistant AML patients.
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PMID:Effects of verapamil on the cellular accumulation of daunorubicin in blast cells and on the chemosensitivity of leukaemic blast progenitors in acute myelogenous leukaemia. 276 4

Verapamil, the calcium-influx-blocking agent, has previously been shown to have favorable interactions with antineoplastic drugs. Our study of human T cell acute lymphatic leukemia (ALL) GM3639 indicates that verapamil enhances the in vitro cytotoxicity of VP-16-213 against drug-sensitive ALL by reducing the concentration of VP-16-213, resulting in 50% cell viability from 104.5 +/- 26.6 nM to 46.0 +/- 2.7 nM (P less than 0.05). The addition of verapamil to VP-16-213 treatment of BDF/1 mice bearing L1210 leukemia increases their mean survival from 21.2 +/- 3.6 to 50.4 +/- 4.3 days (P less than 0.01) and the survival of CD2F/l mice bearing P388 leukemia from 27.8 +/- 3.7 to 49.1 +/- 5.0 days (P less than 0.01). The 30-day survival is significantly increased in L1210 and P388 leukemia mice, and 60-day survival is significantly increased in P388 leukemic mice by verapamil. We developed a vincristine (VCR)-resistant subline of GM3639 T cell ALL, L23, by continuous exposure of drug-sensitive cells to VCR. This subline demonstrates pleiotropic cross resistance to VP-16-213 and daunorubicin. The addition of verapamil to VCR, to VP-16-213, and to daunorubicin completely restores responsiveness to these drugs, as indicated by the normalization of the VCR and VP-16-213 concentrations required for cytotoxicity and the concentration of daunorubicin required for inhibition of thymidine incorporation.
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PMID:Verapamil potentiation of VP-16-213 in acute lymphatic leukemia and reversal of pleiotropic drug resistance. 345 67

We studied the intracellular distribution of drugs within anthracycline-sensitive and -resistant cells by computer-assisted digitized video fluorescence microscopy. We found that the antitumor antibiotic, daunorubicin, distributes differently in anthracycline-sensitive and -resistant human leukemia cells (HL-60). Verapamil and other agents known to circumvent resistance in pleiotropic drug-resistant cell lines were able to change the pattern of distribution of daunorubicin in the anthracycline-resistant HL-60 cells back to the distribution found in anthracycline-sensitive HL-60 cells. To investigate the biochemical basis for this effect, we studied the distribution of daunorubicin and doxorubicin in a hydrophobic/hydrophilic (membrane/cytoplasmic) environment using the two-compartment cell-free system of Folch. Our results demonstrate that various unrelated drugs known to overcome resistance will also change the distribution of the anthracyclines in the hydrophobic/hydrophilic compartments. Our data allow the hypothesis that various unrelated agents known to circumvent resistance may act by altering the hydrophobic/hydrophilic solubility of anthracyclines in the resistant cell.
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PMID:Effect of verapamil and other agents on the distribution of anthracyclines and on reversal of drug resistance. 346 17

Verapamil has been shown to reverse acquired drug resistance to Adriamycin (ADR) and vinblastine in the P388 leukemia and Ehrlich ascites carcinoma model systems. Because of its potential clinical application, we evaluated the ability of verapamil to modulate the effect of ADR and vinblastine on the in vitro cloning of fresh human tumor cells. Fifty-three tumors were cloned in a soft agar system. Continuous exposure to verapamil at concentrations of 1.0, 5.0, and 10.0 micrograms/ml, did not significantly modulate the overall inhibitory activity of ADR and vinblastine (P greater than 0.05). There was no evidence of an effect when results were analyzed by tumor type or previous treatment except in the subgroup of 13 tumors obtained from patients who previously had a clinical response to ADR but were relapsing at the time the tumor specimen was obtained. In this population, at three concentrations of ADR, there was a significant modulation of drug effect (P = 0.10, 0.03, 0.03, respectively). In each subgroup, some tumors showed marked modulation of drug effect by verapamil. These results suggest that the mechanisms of acquired in vivo resistance to ADR may be similar to those occurring in cell lines. However, the effect on human tumors was minor as compared to the results with cell lines. The in vivo significance of this finding remains to be determined.
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PMID:Effect of verapamil on in vitro cytotoxicity of adriamycin and vinblastine in human tumor cells. 356 23

We have examined the effects of verapamil on the cytotoxicity of etoposide, vincristine, and Adriamycin in human leukemia K562 cells as well as in normal human bone marrow granulocyte-macrophage progenitors (CFU-GM). Etoposide was 10-fold more potent against K562 cells than against normal human bone marrow CFU-GM. Similarly, vincristine cytotoxicity was about 10-fold greater against K562 cells than against human bone marrow CFU-GM. In contrast, Adriamycin exhibited little selectivity for K562 cells versus normal bone marrow CFU-GM during the 1-h incubation period of the experiments. In the presence of verapamil (2.5-10 microM), etoposide cytotoxicity was enhanced in both malignant and normal cells. Verapamil enhanced vincristine (0.1 microM) cytotoxicity in K562 cells but did not potentiate Vinca alkaloid toxicity in normal bone marrow CFU-GM. Adriamycin, on the other hand, did not display any calcium antagonist-mediated potentiation of cytotoxicity in either malignant or normal tissue. These results indicate that short-term (1 h) incubations with etoposide, vincristine, and Adriamycin yield different profiles of toxicities whether used alone or with chemosensitizing agents such as the calcium antagonists. These differences in activities are consistent with different mechanisms for intracellular disposition of these three classes of anticancer agents and are worthy of further investigation, especially with regard to combinations with calcium antagonists.
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PMID:Effects of verapamil on etoposide, vincristine, and adriamycin activity in normal human bone marrow granulocyte-macrophage progenitors and in human K562 leukemia cells in vitro. 386 Dec 38

Delivery of the lethal hit signal to target cells (TC) by cytolytic T lymphocyte (CTL) has traditionally been considered strictly dependent upon the presence of external Ca2+ [( Ca2+]ext) in the medium, but neither the role of Ca2+ nor its site of action (effector or target) have been known. We have observed that in different CTL/TC systems the requirement for [Ca2+]ext varies, depending on the target. Some TC, like leukemia L1210, are strictly dependent on [Ca2+]ext for lysis while others, like EL4 (and P815), are not. It is therefore suggested that, where required, [Ca2+]ext exerts its effect(s) on the TC and not the CTL. In support of this conclusion are experiments showing that effector cells cytolytic to certain TC in the absence of [Ca2+]ext, require [Ca2+]ext when used themselves as TC of other effectors. Verapamil, a Ca2+-channel blocker, inhibits the lysis of L1210 but not of EL4 cells, suggesting involvement of Ca2+ flux into L1210 target cells and, if at all involved, Ca2+ mobilization from internal stores in EL4. The different lytic susceptibility of the two TC to the Ca2+ ionophore A23187, in the presence and absence of [Ca2+]ext, correlated with their responses to CTL. It suggests Ca2+ influx into both types of TC in the presence of [Ca2+]ext and its release from internal stores in the lysis of EL4 but not L1210 in the absence of [Ca2+]ext. In view of these results indicating that the target is the site of Ca2+ action, we propose that CTL induce a Ca2+-regulated activation of the TC leading to its lysis.
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PMID:T-Lymphocyte-mediated cytolysis as an excitatory process of the target. I. Evidence that the target cell may be the site of Ca2+ action. 392 77

Overcoming resistance to chemotherapy is an important goal in cancer treatment. In many systems, resistance to anthracyclines and vinca alkaloids correlates with a diminished intracellular content of drug. In P388 leukemia and Ehrlich ascites tumor, an active outward transport of anthracyclines and vinca alkaloids occurs. Calcium channel blockers, such as verapamil, inhibit this active outward transport and increase intracellular content of vinblastine and anthracyclines in cells resistant to vinca alkaloids and anthracyclines, respectively. We report a phase I trial of vinblastine (1.5 mg/m2 daily as iv continuous infusion X 5 days) in 17 patients and concurrent verapamil in escalating doses. Verapamil was administered as a loading dose (0.02-0.1 mg/kg) followed by a maintenance infusion (0.036-0.18 mg/kg/hour) for 5 1/2 days with continuous cardiac monitoring. There was no apparent augmentation of vinblastine toxicity when vinblastine and verapamil were given concurrently. ECG change was the dose-limiting toxicity. At 0.12 mg/kg/hour, five of nine patients developed first-degree heart block (mean P-R interval, 0.32 seconds; range, 0.23-0.52 seconds). Junctional rhythms were noted in two of 17 patients. Reversible nonspecific T-wave changes were seen in four of 17 patients. Blood pressure and left ventricular ejection fractions (ultrasonic) were not altered. Five of 17 patients had wbc count nadirs less than 2000/mm3, and two of 17 patients had platelet count nadirs less than 100,000/mm3. Four patients experienced neurotoxicity. A mean vinblastine concentration of 2.2 ng/ml (0.55 nM) and a mean verapamil concentration of 290 ng/ml (0.45 microM) were achieved with the concurrent 5-day infusion. The tolerable levels of verapamil obtained appear to be less than those which were reported to inhibit vinblastine efflux in vitro. Additional in vitro experiments at the tolerable doses of vinblastine and verapamil are recommended.
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PMID:Phase I study of vinblastine and verapamil given by concurrent iv infusion. 401 89

The calcium antagonists verapamil and nifedipine promote responsiveness to anthracyclines in certain drug-resistant cell lines. Their mode of action involves inhibition of anthracycline exodus, leading to promotion of intracellular drug retention. We examined the relationship between calcium fluxes and anthracycline responsiveness in the P388 murine leukemia, and in a drug-resistant sub-line, P388/ADR. Verapamil and nifedipine promoted daunorubicin accumulation by P388/ADR cells, but this occurred regardless of extracellular calcium concentration and did not involve perturbation of calcium transport. We conclude that these agents promote drug retention via mechanisms not related to calcium ion fluxes.
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PMID:Interactions between calcium antagonists, calcium fluxes and anthracycline transport. 609 54

Several calcium-entry blockers, i.e., verapamil, nifedipine, flunarizine and diltiazem, were evaluated for their effects in models of immediate hypersensitivity disease. Verapamil, flunarizine and diltiazem were all effective in inhibiting antigen-induced bronchospasm in the guinea pig; however, the effects seen were at relatively high doses compared to the doses known to cause cardiovascular effects. Nifedipine caused no significant inhibition of resistance or compliance changes induced by antigen. Flunarizine, verapamil and diltiazem were ineffective in inhibiting antigen-induced histamine release from rat peritoneal mast cells in vitro. Although these compounds were active inhibitors of 5-D-[5,6,8,9,H,12,14,15-3H(N)]-hydroxy-6,8,11,14-eicosatetraenoic acid production in rat basophilic leukemia-1 cells, only flunarizine and verapamil showed effects on the 5-lipoxygenase enzyme when assayed directly. Also, these compounds were ineffective on SRS-A mediated bronchospasm in vivo. These data suggest that the currently available calcium entry blockers have little potential use in immediate hypersensitivity reactions.
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PMID:Evaluation of calcium entry blockers in several models of immediate hypersensitivity. 620 68

A noncytotoxic dose of verapamil, a coronary vasodilator, enhances the cytotoxicity of vincristine (VCR) and vinblastine in P388 leukemia and its VCR-resistant subline, P388/VCR. When 2.2 to 6.6 microM verapamil was added along the VCR to the P388/VCR culture in vitro, VCR resistance was completely overcome. Verapamil in doses of 50 to 100 mg/kg administered daily for 10 days with VCR also enhances the chemotherapeutic effect of VCR in P388- and, especially, P388/VCR-bearing mice. When approximately 3 times the amount of VCR was given to a P388/VCR bearer as compared to a P388 bearer, VCR resistance was almost completely overcome in vivo with 50 to 100-mg/kg doses of verapamil. The amount of VCR incorporated into P388 cells was larger than that in P388/VCR cells. Verapamil (6.6 microM) enhanced the cellular level of VCR in P388 cells 2-fold and enhanced the level of VCR in P388/VCR cells 10-fold. The amount of VCR in P388/VCR cells reached the same level as that found in P388 cells. The overcoming of VCR resistance in vivo and in vitro could be explained by the effective accumulation of VCR by verapamil in P388/VCR cells mediated by the inhibition of a VCR efflux function of the cells, a mechanism which remains to be solved.
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PMID:Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. 721 65


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