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)

Razoxane is one of the few agents which has shown activity in the treatment of advanced colorectal cancer. The drug has therefore been evaluated in a prospective randomized controlled trial as an adjuvant to surgery for resectable colorectal cancer. The results to median follow-up of 5 years are reported here. Accrual has ceased and a total of 272 patients entered the trial (133 control, 139 treatment). Treated patients received razoxane postoperatively on a continuous, long-term basis while control patients received identical clinical care but no adjuvant chemotherapy. Analysis of the results shows a significant prolongation of the time to recurrence for Dukes' C patients. All other groups including the overall analysis show no benefit although there is a consistent trend in favour of the treated patients except in Dukes' group 'D'. Razoxane is tolerated well by patients and causes minimal side-effects. However acute leukaemia occurred in three patients (2.45 per cent) after prolonged exposure to the drug and further evaluation should be in patients who are at high risk of developing recurrent cancer, in whom such a risk may be acceptable. It is concluded that razoxane is suitable for further evaluation in colorectal cancer and for incorporation into combination chemotherapy regimens.
 ...
PMID:Randomized trial of oral adjuvant razoxane (ICRF 159) in resectable colorectal cancer: five-year follow-up. 352 84

The bisdioxopiperazines ICRF-187 (dexrazoxane), ICRF-193, and ICRF-154 are catalytic noncleavable complex-forming inhibitors of DNA topoisomerase II that do not produce protein-linked DNA strand breaks. In this study, we showed that bisdioxopiperazines induced erythroid differentiation, inhibited human leukemia K562 cell growth, and caused a slow induction of apoptosis. Dexrazoxane treatment caused DNA endoreduplication resulting in large highly polyploid cells. This result suggested the lack of a DNA topoisomerase II activity-based cell cycle checkpoint. The percentage of K562 cells that became apoptotic was much larger than the percentage of cells that stained for hemoglobin, suggesting that prior differentiation was not required for induction of apoptosis. Use of the Bcr-Abl tyrosine kinase inhibitor STI-571 resulted in a reduction in Bcl-xL levels and potentiation of dexrazoxane-induced apoptosis related to an earlier onset and more extensive cleavage of caspase-3. These results indicated that dexrazoxane-induced apoptosis is associated with a caspase-3 activation/cleavage pathway. In addition, these results were consistent with the antiapoptotic signaling function of Bcr-Abl to regulate expression of Bcl-xL. The ability of dexrazoxane to induce differentiation and apoptosis suggests that bisdioxopiperazines may be useful in treating some types of leukemia.
 ...
PMID:The catalytic DNA topoisomerase II inhibitor dexrazoxane (ICRF-187) induces differentiation and apoptosis in human leukemia K562 cells. 1117 39

Anthracyclines have been the backbone of acute leukemia therapy in the adult for many years, but little attention has been paid to the long-term toxicity of these agents in this disease because of the poor survival of this population of patients. Recent studies have examined dose-intensified daunorubicin with dosages as high as 95 mg/m2 daily x 3 in this population with the attendant concerns of both acute and chronic toxicity. We have examined three human leukemia cell lines in vitro, treated with either daunorubicin, mitoxantrone, with or without cytosine arabinoside in the presence of dexrazoxane to determine whether such treatment would be synergistic or antagonistic. AML-193, CRF-SB, and Molt-4 cell lines were grown to confluence, plated into microtiter dishes and incubated for 72 h with varying concentrations of the above drugs. Cytotoxicity was determined by the MTT assay, and synergy or antagonism by median effect analysis. Dexrazoxane demonstrated additive or synergistic cytotoxic effects (CI <1) under most conditions. The triplet of daunorubicin, cytosine arabinoside, and dexrazoxane showed profound synergy in all three cell lines. These effects occurred at clinically achievable levels. If high dosages of anthracyclines are contemplated in this population, these preclinical data suggest that the addition of dexrazoxane to classical therapy is not antagonistic and thus may allow an investigation of the role of dexrazoxane as a cardiac protectant.
Leukemia 2001 Oct
PMID:In vitro effects of dexrazoxane (Zinecard) and classical acute leukemia therapy: time to consider expanded clinical trials? 1158 8

Doxorubicin is the most widely studied agent for the treatment of malignant mesothelioma. In conventional doses, the response rate is approximately 17%. Higher dose doxorubicin has been successfully employed in other tumor types. Dexrazoxane has been demonstrated to reduce the cardiac toxicity associated with long term, chronic use of doxorubicin. Based upon phase I data generated by the Cancer and Leukemia Group B (CALGB) indicating that doxorubicin at a dose of 120 mg/m(2) when combined with dexrazoxane and GM-CSF could be safely administered, the CALGB undertook a phase II study of high-dose doxorubicin in patients with malignant mesothelioma. Toxicity was excessive, necessitating protocol modification and ultimately protocol termination. There were no objective responses observed. We conclude that high-dose doxorubicin administered with dexrazoxane is unacceptably toxic in this patient population.
 ...
PMID:High-dose doxorubicin, dexrazoxane, and GM-CSF in malignant mesothelioma: a phase II study-Cancer and Leukemia Group B 9631. 1167 88

Dexrazoxane (DEX) prevents the formation of free radical, lipid peroxidation and cardiotoxicity caused by anthracyclines. Due to a concern about its possible interference with anthracyclin cytotoxicity, the in vitro effect of DEX on daunorubicin (DNR) cytotoxicity, cell cycle and induction of apoptosis by annexin-V was investigated. The sensitivity to DEX, DNR and their combination was tested by the MTT assay in human promyelocytic leukemia HL-60, the erythroid blast crisis CML K562 cell lines and in 45 children with ALL and AML. Cell cycle analysis and annexin-V expression were performed by flow cytometry. It has been observed that DEX itself weakly, but significantly caused cytotoxicity in both cell lines and in patient samples, especially in initial ALL samples. DEX sensitized K562 and HL60, but not patient samples, to cytotoxicity of DNR. The percentage of necrotic/apoptotic cells, as detected in cell cycle analysis and annexin V staining, was higher after exposure to DEX +/- DNR, when compared to respective samples not treated with DEX, in both cell lines but not in patient samples. Expression of annexin V induced by DEX in both cell lines was enlarged, regardless of the presence of DNR. This difference was not observed in patient samples, however, the number of cells expressing annexin V was higher after exposure to DEX +/- DNR in comparison to respective samples not treated with DEX. In conclusion, it seems that DEX possibly has no impact on the sensitivity of childhood leukemic blasts to DNR, however, has weak cytotoxic properties itself.
Leukemia 2002 May
PMID:Dexrazoxane has no impact on sensitivity of childhood leukemic blasts to daunorubicin. 1198 42

Treatment advances have increased survival in children with cancer, but subclinical, progressive, irreversible, and sometimes fatal treatment-related cardiovascular effects may appear years later. Cardio-oncologists have identified promising preventive and treatment strategies. Dexrazoxane provides long-term cardioprotection from doxorubicin-associated cardiotoxicity without compromising the efficacy of anticancer treatment. Continuous infusion of doxorubicin is as effective as bolus administration in leukemia treatment, but no evidence has indicated that it provides long-term cardioprotection; continuous infusions should be eliminated from pediatric cancer treatment. Angiotensin-converting enzyme inhibitors can delay the progression of subclinical and clinical cardiotoxicity. All survivors, regardless of whether they were treated with anthracyclines or radiation, should be monitored for systemic inflammation and the risk of premature cardiovascular disease. Echocardiographic screening must be supplemented with screening for biomarkers of cardiotoxicity and perhaps by identification of genetic susceptibilities to cardiovascular diseases; optimal strategies need to be identified. The health burden related to cancer treatment will increase as this population expands and ages.
...
PMID:Cardiovascular disease in adult survivors of childhood cancer. 2558 48

Anthracyclines constitute the backbone of intensive adult acute myeloid leukemia (AML) therapy. Cardiotoxicity is one of its most serious adverse effects, and its incidence increases with cumulative dose. Dexrazoxane is a cardioprotective agent used in conjunction with anthracycline therapy. There is limited data of its usage in adult AML patients. We report the outcomes of six older adults at high risk of anthracycline-induced cardiotoxicity who received dexrazoxane during induction/re-induction therapy. Five had preserved left-ventricular function while two proceeded onto stem-cell transplantation. Additional investigation of dexrazoxane in adult leukemia therapy is warranted, particularly in older patients at highest risk for cardiovascular mortality.
 ...
PMID:Dexrazoxane for cardioprotection in older adults with acute myeloid leukemia. 2846 84

Idarubicin is an anthracycline antileukemic agent widely used in the treatment of hematological malignancies. However, cardiotoxicity and secondary leukemia have been reported after idarubicin treatment. Dexrazoxane is the only medication approved by FDA to prevent anthracycline-evoked cardiotoxicity. However, lack of information on the genomic damage caused by the combination of these 2 drugs prompted us to conduct the current study. We treated mice with different doses of idarubicin and/or dexrazoxane. Genomic DNA damage, apoptosis, and reactive oxygen species (ROS) were evaluated in the bone marrow cells. Our results demonstrate that mice pretreated of with dexrazoxane had significant lower genomic damage, apoptosis and ROS generation compared with that of mice treated with idarubicin alone, an effect that was dependent on dexrazoxane dose. The expression of 84 genes implicated in DNA damage-signaling pathways was quantified using an RT2 Profiler PCR Array. Idarubicin treatments altered the expression of 58 genes, and 16 of those were expressed at significantly different level. In treatments combining idarubicin and dexrazoxane, substantial restorations of mRNA expression of these genes were observed. RT-qPCR was performed for selected genes and the alteration of these genes was confirmed. Alterations in mRNA expression of a subset of genes were further proved by Western blotting analysis of protein levels, which nearly showed similar alterations. Conclusively, dexrazoxane can be safely co-administered with idarubicin. Moreover, dexrazoxane minimizes idarubicin-evoked genomic damage via its radical scavenging and DNA repair-enhancing activities. Thus, dexrazoxane may help avert secondary malignancies in cancer patients in remission who are exposed to idarubicin.
 ...
PMID:Dexrazoxane Averts Idarubicin-Evoked Genomic Damage by Regulating Gene Expression Profiling Associated With the DNA Damage-Signaling Pathway in BALB/c Mice. 2897 40