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)

Forty-four cases of essential thrombocytosis (ET) were diagnosed in the last 20 years, 19 males and 24 females (M/F: 0.76), aged between 3 and 86 years (median, 62 years), and 9 of them being under 40 years of age. The M/F ratio for patients under 60 years was 0.5, whereas it was 1.09 for patients over 60. The clinical forms at onset were: asymptomatic, 36.5%; as a bleeding disorder (BD), 20.4%; as thrombotic disease (TD) 22.7%; BD/TD, 13.6%, and others, 6.8%. The most important biological features included platelet count over 1.000 x 10(9)/L (59.1%), abnormal platelet aggregation, chiefly with ADR (56.5), mild reticulin myelofibrosis (55%), abnormal karyotype (2.6%), moderately high LDH levels (56.8%) and pseudo-hyperkalaemia (40%). The initial therapeutic approach was: observation (12 cases), antiaggregating agents (6 cases), and chemotherapy (BSF, HU, etc.) in the remainders. One patient evolved quickly into acute myelogenous leukaemia and two others suffered a late transformation into polycythaemia vera (PV) and myeloid metaplasia, respectively. The median survival was over 11 years, this being longer in patients under 60 years of age, in those with platelet count at diagnosis between 600 and 1000 x 10(9)/L and in those without initial symptoms of thrombosis. The advent of electronic blood-cell counters has made ET no longer a rare chronic myeloproliferative disease, its incidence coming now closer to that of PV; thus, in the last four quinquennial periods the incidence of ET/PV has evolved as following: 1/19, 4/16, 13/18 and 26/29.
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PMID:[Essential thrombocythemia: a myeloproliferative state on the rise. Clinico-biological study and course of 44 cases]. 158 33

We investigated the effects of seven isoquinoline derivatives in overcoming resistance to vinblastine in Adriamycin-resistant mouse leukemia P388/ADR cells and human myelogeneous leukemia K562/ADR cells. N-(2-Methylpiperazyl)-5-isoquinoline-sulfonamide (H-7), N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide (H-8), and N-(2-aminoethyl)-5-isoquinolinesulfonamide (H-9) did not reverse resistance to vinblastine in these resistant cells. N-[2-[N-[3-(4-Chlorophenyl)-2-propenyl]amino]ethyl]-5- isoquinolinesulfonamide (H-86) and N-[2-[N-[3-(4-chlorophenyl)-1-methyl-2-propenyl]- amino]ethyl]-5-isoquinolinesulfonamide (H-87) caused significant accumulation of intracellular vinblastine and marked reversal of the resistance to vinblastine in both resistant cell lines. Addition of a formyl group at the terminal amino group of H-86 (H-85) or addition of an aminoethyl group to the nitrogen atom at the sulfonamide group of H-86 (W-66) reduced those activities. The activity on vinblastine accumulation seems to correlated with the hydrophobicity of the compounds. The compounds that effectively reversed resistance to vinblastine inhibited [3H]vinblastine efflux and photoaffinity labeling of P-glycoprotein with a photosensitive analogue of vinblastine, N-(p-azido-(3-[125I]iodo)-salicyl)-N'-beta-aminoethylvindesine. Although these isoquinoline derivatives inhibited protein kinase A and protein kinase C with various potencies, these inhibitory activities did not correlate with the reversal of drug resistance. These results indicate that hydrophobic isoquinoline derivatives reverse multidrug resistance due to the suppression of drug binding to P-glycoprotein, without involvement of their activities on protein kinase A and protein kinase C.
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PMID:Overcoming of vinblastine resistance by isoquinolinesulfonamide compounds in adriamycin-resistant leukemia cells. 161 7

Cytotoxic effects of vitamin K3 were evaluated utilizing the P388/S, L1210, EAT, S-180 and a multidrug-resistant variant of the P388 leukemia cells (P388/ADR). Antitumorigenic potential of vitamin K3 was assessed by MTT and DNA and RNA biosynthesis inhibition assay. A dose-dependent inhibition of P388/S and P388/ADR cell survival and [3H]thymidine and [3H]uridine incorporation (as a function of DNA and RNA biosynthesis) was observed in tumor cell types exposed to vitamin K3 concentrations ranging from 1 to 100 microM. One hundred mg/kg vitamin K3 caused a 32 and 52% increase in life span of the sensitive and resistant P388 leukemia tumor-bearing mice. Induction of DNA strand breaks at 100 microM vitamin K3 was greater in P388/S than in P388/ADR cells. In vitro treatment with vitamin K3 (100 microM) reduced the intracellular levels of GSH by 40, 47, 6, 15 and 14% in P388/S, P388/ADR, EAT, S-180 and L1210 tumor cells, respectively. In vivo treatment with 100 mg/kg vitamin K3 reduced the GSH content by 18 and 38% and increased the activity of the enzyme GSH-S-transferase and gamma-glutamyl transpeptidase. Effects of free radical scavengers and of compounds that modulate the GSH metabolism on the cytotoxicity of vitamin K3 were also investigated. Results indicate that vitamin K3 interacts with the tumor cell thiol pools while eliciting its antitumor effects and suggest the utility of vitamin K3 in dealing with the growing problem of multidrug resistance.
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PMID:Modulation of thiol pools by vitamin K3 and its effect on survival of sensitive and resistant murine tumor cells. 168 89

MOPP (mechlorethamine, vincristine, procarbazine, prednisone) was the first successful regimen for the treatment of Hodgkin's disease. It has the longest period of follow-up and is best studied as to its benefits and acute and long-term side effects. The acute toxicity of the side effects, including nausea and/or vomiting, hair loss, and myelosuppression, may have been reason to modify doses of nitrogen mustard, an agent whose dose intensity may be critical in achieving long-term benefits. The substitution of chlorambucil and vinblastine in the ChlVPP (chlorambucil, vinblastine, procarbazine, prednisone) program has relieved all of these acute toxicities, except myelosuppression. The long-term toxicity of sterility, especially in males, and myelodysplasia is most likely due to alkylating-agent toxicity and would not be influenced by the various MOPP variants, such as MVPP (mechlorethamine, vinblastine, procarbazine, prednisone), ChlVPP, and COPP (chlorambucil-vincristine, procarbazine, prednisone). Doxorubicin-containing regimens, such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and ABDIC (doxorubicin, bleomycin, dacarbazine, lomustine, prednisone), have been second-line treatments that have significant antitumor effect and, as such, have resulted in few, if any, long-term cures in most series. ABVD has been incorporated into alternating MOPP/ABVD schemes or in hybrids that attempt to offer all active agents, such as MOPP/ABV. The initial experience has been encouraging with high and durable complete remissions (CRs). MOPP/ABVD x 12(1) and MOPP-2/ABVD-2(2) have been compared with MOPP alone with a significant superiority for the alternating regimens. Other randomized trials have not shown any superiority for the alternating program. The Cancer and Leukemia Group B (CALGB) has compared MOPP with MOPP/ABVD given with a third arm of ABVD alone. The complete response and time-to-treatment failure rates for MOPP/ABVD and ABVD alone were superior to those for MOPP. Significant modifications of MOPP doses may explain the differences, since only 20% of patients were receiving full doses of nitrogen mustard by the sixth dose. ABVD has unique toxicity, and myelodysplasia and sterility are not seen. Pulmonary fibrosis with radiation and bleomycin is unique to ABVD, as shown in the ABVD experience at the NCl (Milan). Can ABVD be improved? The demonstrated single-dose activity of etoposide in Hodgkin's disease has prompted its inclusion in second-line programs, such as EVA (etoposide, vincristine or vinblastine, doxorubicin). The second-line response rates in the St Bartholomew's (London, England) series (where vincristine was used) was 11 of 19 patients (58%);3 in the ongoing CALGB trial of EVA (vinblastine combination), the response rate is 67%. (ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Can MOPP be replaced in the treatment of advanced Hodgkin's disease? 168 9

Vitamin K3 was employed as a resistance-modifying agent to investigate its activity in enhancing mitoxantrone (MITO)-induced cytotoxicity in parental (P388/S) and multidrug resistant (P388/ADR) P388 leukemia cells. Vitamin K3 potentiated the antitumor effects of MITO in P388/S and P388/ADR tumor cells as monitored by inhibition of tumor cell survival (MTT assay). MITO and vitamin K3 in combination effected an enhanced inhibition of [3H]thymidine (DNA synthesis) and [3H]uridine (RNA synthesis) and also increased the life span of the sensitive and resistant tumor-bearing animals. The effect of vitamin K3 on the induction of DNA strand breaks by MITO was also examined. Increased fragmentation of DNA was illustrated in the sensitive and resistant P388 leukemia cells exposed to the combination. Observations indicate the restoration of sensitivity in P388/ADR cells to MITO by vitamin K3 that may be due to its ability to increase the MITO-induced DNA strand breaks.
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PMID:Antiproliferative effects of mitoxantrone in ADR-sensitive and ADR-resistant P388 leukemia cells enhanced by vitamin K3. 180 14

Doxorubicin is an essential component of the treatment of aggressive lymphoma, childhood solid tumors, bone and soft tissue sarcomas, and breast cancer and additional indications are emerging. On the other hand, daunorubicin has occupied the central position of interest in the treatment of acute leukemia. Epirubicin has a spectrum very similar to doxorubicin but lesser toxicity. The ability to protect against cardiotoxicity with ICRF-187 further enhances clinical interest in exploiting modifications in doze intensity to therapeutic advantage. Idarubicin has at least equivalent activity to daunorubicin and doxorubicin in leukemia. New areas of research in relation to anthracycline antibiotics include introduction of new the analogs, insight into mechanisms of resistance, the reversal of multidrug resistance in vitro, the protection of cardiac toxicity, and the study of other important biochemical reactions relevant to cytotoxicity. Orally active anthracyclines such as idarubicin and compounds which lack cross-resistance with the parent drugs or have other mechanisms for cytotoxicity are being developed. It is likely that these modifications will lead to an expanding therapeutic spectrum for these already widely useful drugs.
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PMID:New anthracycline antitumor antibiotics. 183 87

Itraconazole is a recently developed triazole antifungal agent that inhibits cell membrane sterol biosynthesis. Itraconazole, in a dose-dependent manner, enhanced intracellular accumulation of daunorubicin and reversed the drug resistance in murine leukemia P388/ADR cells. In addition, itraconazole corrected the altered plasma membrane potentials of P388/ADR cells. The concentrations of itraconazole that reversed drug resistance are comparable to the plasma levels achieved by therapeutic dosage used in the treatment of fungal infections. Therefore, itraconazole is a potential candidate for in vivo use to reverse multidrug resistance in cancer with added benefit of its antifungal property.
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PMID:Reversal of daunorubicin resistance in P388/ADR cells by itraconazole. 184 51

Cytocidal effects of combined use of BH-AC and nitrosourea derivatives (MCNU, and ACNU) were evaluated in vitro against adriamycin-resistant human leukemia cell line (K-562/ADR-I). K-562/ADR-I cells were resistant to six kinds of agents (vindesine, mitoxantrone, aclacinomycin, cisplatin, MCNU, and BH-AC) of 14 agents tested and this cell line proved to be a multi-drug resistant line. Combined use of BH-AC and MCNU did not achieve additive effects on K-562, parent cell line and BH-AC and MCNU were less effective to K-562/ADR-I by single use. However, combination of BH-AC and MCNU showed additive effects. These results supported the evidence that combination of BH-AC with MCNU was effective in patients with multi-drug resistant malignant lymphomas.
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PMID:[In vitro effect of combined use of BH-AC and nitrosourea derivatives against adriamycin-resistant human leukemia cell line]. 195 59

We previously developed a mathematical model to describe the emergence and dynamic growth of a drug-resistant subpopulation in a tumor. In the present study, our objective was to test the model's ability to mimic two strategies for reversal of drug resistance. We present data from one in vitro cell proliferation assay with drug-resistant LS174T human colon carcinoma variants and one in vivo assay of survival after treatment of female (C57BL/6 x DBA/2)F1 mice inoculated with doxorubicin-resistant P388/ADR leukemia cells. The in vitro assay examined the effects of inhibiting the biosynthesis of glutathione in cells resistant to alkylating agents or cisplatin. The in vivo assay compared the effects on cell survival of low-level continuous infusion versus high-intensity bolus dosing, with or without coadministration of the drug efflux pump blocker verapamil. Results in vitro and in vivo were comparable for qualitative accuracy and predictability to results with the model. Both the in vitro study and the model showed that, for resistant cells with high levels of glutathione, short-term cell survival was dose dependent and that even high doses of drug did not eliminate all of these cells. Addition of an inhibitor of glutathione biosynthesis did, however, augment elimination of the resistant cells. Resistant cells with low levels of glutathione could be eliminated with high drug doses or coadministration of drug and a glutathione synthesis inhibitor. In vivo, coadministration of doxorubicin with verapamil increased animal survival when either continuous infusion or bolus dosing regimens were used. The effectiveness of the blocker is crucial; when a partially (50%) effective blocker is used, continuous infusion achieves better elimination of resistant cells, but a completely (100%) effective blocker is efficacious in both dosing scenarios. Careful interpretation of these findings is necessary because the pharmacokinetics of drug in the small populations of cells in the model are not easily extrapolated to those in large tumors. This model may be useful in determining resistance mechanisms, their levels of effectiveness, and concentrations of compounds required at target sites to overcome them.
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PMID:Drug resistance-reversal strategies: comparison of experimental data with model predictions. 196 Jul 54

Electron microscopy of cultured P388 leukemia cells revealed morphological differences between the Adriamycin-resistant (P388/ADR) and -sensitive (P388/0) cell lines. P388/ADR cells showed longer villus-like protrusions and large foldings of the plasma cell membrane, whereas P388/0 cells had only short membrane protrusions. Western blot analysis of cells revealed the increased expression of a glycoprotein of 170-180 kDa (P-glycoprotein) in P388/ADR cells as compared with P388/0 cells, which is consistent with the findings of other studies. A modulation of the membrane morphology of in vitro P388/ADR cells was evident from one i.p. in vivo passage for 10 days, by a reversion to the non-ruffled sensitive-cell morphology. Long-term P388/ADR culture cells showed a reduction in membrane folding with as little as a 4-h exposure to the peritoneal ascitic fluid obtained when the tumor was harvested. However, there was no alteration in the expression of P-glycoprotein or in the sensitivity to Adriamycin in either of the P388 cell lines when grown in vivo or when exposed to ascites fluid from an i.p. tumor. Thus, the modulation of membrane morphology was related to the tumor cell environment rather than the abundance of P-glycoprotein in the plasma membrane.
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PMID:P-glycoprotein expression and modulation of cell-membrane morphology in adriamycin-resistant P388 leukemia cells. 196 28


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