Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The oral antitumor drugs against hematological malignancies are summarized. Sobuzoxane, a topoisomerase II inhibitor, is useful for the treatment of lymphoma, especially adult T cell leukemia/lymphoma. Sobuzoxane has an effect to protect against doxorubicin cardiotoxicity. Cytarabine ocfosfate, a derivative of cytosine arabinoside, is a useful agent against acute leukemia and MDS, especially RAEB, RAEB in T, CMMoL. The JALSG AML 92 study for APL with all-trans retinoic acid resulted in a 89% CR rate in 196 and 64% 4-year DFS in CR cases. Hydroxycarbamide is can control the WBC in CML. This agent is also effective for other myeloproliferative disorders, such as acute leukemia and MDS. Oral administration of 50 mg etoposide daily showed a good outcome in old patients with malignant lymphoma. For old patients and those with refractory hematological malignancies, oral administration of these agents can offer a new form of palliative therapy to allow them to remain at home while maintaining a high quality of life.
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PMID:[Oral antitumor drugs for hematological malignancies]. 1006 91

NAD(P)H:quinone oxidoreductase (NQO1) converts benzene-derived quinones to less toxic hydroquinones and has been implicated in benzene-associated hematotoxicity. A point mutation in codon 187 (Pro to Ser) results in complete loss of enzyme activity in homozygous subjects, whereas those with 2 wild-type alleles have normal activity. The frequency of homozygosity for the mutant allele among Caucasians and African Americans is 4% to 5% but is higher in Hispanics and Asians. Using an unambiguous polymerase chain reaction (PCR) method, we assayed nonmalignant lymphoblastoid cell lines derived from 104 patients with myeloid leukemias; 56 had therapy-related acute myeloid leukemia (t-AML), 30 had a primary myelodysplastic syndrome (MDS), 9 had AML de novo, and 9 had chronic myelogenous leukemia (CML). All patients had their leukemia cells karyotyped. Eleven percent of the t-AML patients were homozygous and 41% were heterozygous for the NQO1 polymorphism; these proportions were significantly higher than those expected in a population of the same ethnic mix (P =.036). Of the 45 leukemia patients who had clonal abnormalities of chromosomes 5 and/or 7, 7 (16%) were homozygous for the inactivating polymorphism, 17 (38%) were heterozygous, and 21 (47%) had 2 wild-type alleles for NQO1. Thus, NQO1 mutations were significantly increased compared with the expected proportions: 5%, 34%, and 61%, respectively (P =.002). An abnormal chromosome no. 5 or 7 was observed in 7 of 8 (88%) homozygotes, 17 of 45 (38%) heterozygotes, and 21 of 51 (41%) patients with 2 wild-type alleles. Among 33 patients with balanced translocations [14 involving bands 11q23 or 21q22, 10 with inv(16) or t(15;17), and 9 with t(9;22)], there were no homozygotes, 15 (45%) heterozygotes, and 18 (55%) with 2 wild-type alleles. Whereas fewer than 3 homozygotes were expected among the 56 t-AML patients, 6 were observed; 19 heterozygotes were expected, but 23 were observed. The gene frequency for the inactivating polymorphism (0. 31) was increased approximately 1.4-fold among the 56 t-AML patients. This increase was observed within each of the following overlapping cohorts of t-AML patients: the 43 who had received an alkylating agent, the 27 who had received a topoisomerase II inhibitor, and the 37 who had received any radiotherapy. Thus, the frequency of an inactivating polymorphism in NQO1 appears to be increased in this cohort of myeloid leukemias, especially among those with t-AML or an abnormality of chromosomes 5 and/or 7. Homozygotes and heterozygotes (who are at risk for treatment-induced mutation or loss of the remaining wild-type allele in their hematopoietic stem cells) may be particularly vulnerable to leukemogenic changes induced by carcinogens.
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PMID:Prevalence of the inactivating 609C-->T polymorphism in the NAD(P)H:quinone oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid leukemia. 1039 48

The t(3;21)(q26;q22) is a recurring chromosomal abnormality in blastic crisis of chronic myelogenous leukemia (CML) and in therapy-related myelodysplastic syndrome and acute leukemia. In order to clarify the genetic recombination mechanism underlying the t(3;21), we molecularly cloned the breakpoints and determined their nucleotide sequence in a case of CML in blastic crisis with t(3;21). Near the breakpoint on chromosome 21, three homopyrimidine (CT)-rich sequences were found. We also identified a sequence homologous to the topoisomerase II binding and cleavage consensus sequence surrounding the breakpoint on chromosome 3, and two topoisomerase II binding and cleavage consensus sequences near the breakpoint on chromosome 21. In addition, around the breakpoint on chromosome 21, four chi-like sequences, potential consensus signals for activating recombination, were found. There were no Alu sequences or antigen receptor gene-like heptamer/nonamer signal sequences within the breakpoints on chromosomes 3 and 21. The breakpoints were found adjacent to the topoisomerase II binding and cleavage consensus sequence or the homopyrimidine-rich sequence. Furthermore, the chi-like sequences and the homopyrimidine-rich sequence were detected on chromosome 21 but not on chromosome 3. Genes Chromosomes Cancer 26:92-96, 1999.
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PMID:Molecular characterization of the genomic breakpoints in a case of t(3;21)(q26;q22). 1044 Oct 11

Drug resistant cells often have an increased capacity to repair their DNA after damage by cytotoxic agents. Aphidicolin can inhibit this DNA repair. We describe a study of the effect of aphidicolin to modulate the sensitivity to cytotoxic drugs of blast cells from 13 patients with AML, 11 with de novo disease on presentation and 2 secondary to MDS. Three patients had relapsed following previous therapy and samples were received from 1 patient both on presentation and relapse. Blast cells were exposed to anthracyclines, antimetabolites or etoposide +/- aphidicolin (15 microM) for 48 hours. The MTT assay was used to measure cell survival and the LC50 (concentration of drug required for 50% cell kill) was calculated. Overall, there was a significant increase in sensitivity to ara-C on co-incubation with aphidicolin in 12/14 samples (p = 0.007). The median increase in sensitivity was 3.88-fold (range 1.26- to 80-fold). Interestingly, when patients were grouped according to in vitro sensitivity to ara-C, cells from resistant patients demonstrated the greatest increase in sensitivity (median 14-fold compared to 2-fold for the sensitive group, p = 0.02). Despite the documented evidence for altered DNA repair as a mechanism of resistance to the topoisomerase II inhibitors, we found no significant increase in sensitivity to daunorubicin, doxorubicin or etoposide on co-incubation with aphidicolin. Nevertheless, we believe the unparalleled modulation of ara-C warrants further investigation.
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PMID:Aphidicolin markedly increases the in vitro sensitivity to ara-C of blast cells from patients with AML. 1050 Aug 35

Clinically distinct features in both alkylating agents--and topoisomerase II (topo II)-induced secondary leukemias (SL) are reviewed with special reference to the increasing frequencies observed in relation to advances in modern cancer chemotherapy. Topo II interacts with, and then stabilizes the cleavable complex that ultimately results in double strand breaks. In patients with SL, breakpoints in MLL gene are clustered within SARs of 3' bcr. However, mechanisms by which the former type of SL is caused remain to be elucidated. Since alkylating agents often induce profound marrow dysplasia, long-lived lesions induced on hematopoietic stem cells are of potential relevance to the development of SL. This process may be partially demonstrated by the variety of mitotic modifications found in MDS. Recently, the association has been investigated between certain enzyme polymorphisms related to activation or detoxification of anticancer agents and SL. These studies have potential importance, since individuals with a certain genotype may be at increased risk for SL.
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PMID:[Secondary leukemias: their clinical features, incidence among populations at risk, mechanisms and new strategy for prediction]. 1058 63

The frequency of leukemia and myelodysplasia following treatment with cytotoxic agents is increasing. Theses treatment-related leukemias raise both theoretical and practical concerns. On a theoretical basis, cytogenetic and molecular abnormalities described constitute useful models to study leukemogenesis. On a practical basis, prognosis of treatment related-leukemia is somehow unfavorable and implies to take in account this risk in the development of combination therapy for solid tumors or hematological malignancies. There are two distinctive types of treatment-induced leukemia: those secondary after alkylating agents and those secondary after topoisomerase-II- inhibitors. These two types of leukemia after regarding their clinical and their hematological characteristics, but also regarding their prognosis and their associated molecular abnormalities. Leukemias induced by alkylating agents occur generally 5 or 6 years after the beginning of the chemotherapy and are preceded by a more or less long phase of pancytopenia or myelodysplasia and according to their cytologic aspects are difficult to be classified within FAB classification. Their prognosis is pejorative. The most commonly found cytogenetic abnormalities associated with these types of induced leukemia are losses or deletions of chromosomes 5 and 7. Leukemias induced by topoisomerase-II-inhibitors occur shortly after the treatment (12 to 30 months), they begin generally suddenly without preleukemia prodom and their more frequent cytological aspects are M4 and M5 type. The prognosis is less severe than alkylating agent related forms with higher response rates and is dependant of discovered cytogenetic abnormalities. The more frequent molecular abnormalities are not chromosome deletions but balanced translocations. They affect particularly the MLL gene located at band 11q23. Other translocations have been described in this type of leukemia and are comparable to the one found in the de novo leukemia (t8;21, t15;17) for example. The evaluation of the risk of treatment-related leukemia for a given chemotherapeutic agent is difficult as for as current treatment use the combination of several agents potentially leukemogenic (chemotherapy and radiotherapy, combination chemotherapy). It is necessary to set up an up-dated data register in order to centralize all therapy-related myelodysplasia and leukemia within the treatment of a given type of cancer.
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PMID:[Leukemias induced by anticancer chemotherapies]. 1058 9

Cisplatin appears to be the major cause for long-term toxicity in patients treated for testicular cancer. Long-term side effects consist mainly of nephrotoxicity, ototoxicity, and neurotoxicity as well as gonadal damage. Following standard-dose chemotherapy approximately 20% to 30% of patients will be affected by long-term side effects, although not all these side effects will cause an impaired quality of life. Several strategies have been or currently are being evaluated to reduce acute and long-term complications including the introduction of equally effective, but less toxic regimens, or the use of cytoprotective agents such as amifostine. Secondary acute myeloid leukemia and secondary myelodysplastic syndrome probably represent the worst possible long-term complications of cancer therapy in those patients who originally were cured of their primary testicular cancer. Therapy-related solid tumors are mainly associated with the use of radiation therapy and the risk for developing a therapy-related solid tumor is increased approximately two to three times compared to the general population. In contrast, therapy-related leukemias are predominantly associated with chemotherapy, particularly with the use of topoisomerase-II inhibitors and alkylating agents. In general, the cumulative incidence of therapy-related leukemia following treatment of germ cell cancer is low. It is approximately 0.5% and 2% at 5 years of median follow-up for patients receiving etoposide at cumulative doses< or = 2 g/m(2) and >2 g/m(2), respectively. The risk-benefit analysis in patients with testicular cancer clearly favors the use of current treatment regimens including high-dose chemotherapy. However, even the acceptably low number of therapy-related long-term complications should encourage the search for equally effective but less toxic therapies. This review will highlight important available data about therapy-related toxicity and particularly, therapy-related malignancies following cisplatin-etoposide-based chemotherapy.
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PMID:Late toxicity following curative treatment of testicular cancer. 1058 57

Given the young age at which testicular cancer is treated and the excellent prognosis for patients suffering from this disease, therapy-related malignancies represent a significant problem. Therapy-related solid tumors are associated mainly with the use of radiation therapy. The risk for developing a therapy-related solid tumor is approximately 2- to 3-fold increased compared with the general population. Therapy-related leukemias are associated predominantly with chemotherapy, particularly with the use of topoisomerase-II inhibitors and alkylating agents. In general, the cumulative incidence of therapy-related leukemia is low. It is approximately 0.5% and 2% at 5 years of median follow-up for patients receiving etoposide at cumulative doses < or = 2 g/m2 and > 2 g/m2, respectively. High cumulative doses of etoposide given over a short period of time appear to be less leukemogenic than a similar dose of etoposide given over a longer period of time. There might, additionally, be a synergistic effect of cisplatin and etoposide on the induction of therapy-related leukemia. For patients who receive high-dose chemotherapy with autologous stem-cell support, the risk of therapy-related myelodysplastic syndrome and leukemia appears to be substantially lower compared with that reported in non-Hodgkin's lymphoma patients undergoing high-dose chemotherapy. The transplantation procedure itself does not appear to add to the therapy-related leukemia risk. The risk-benefit analysis in patients with testicular cancer clearly favors the use of current treatment regimens including high-dose chemotherapy. However, even the acceptably low number of therapy-related leukemias should encourage the search for equally effective but less toxic therapies.
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PMID:Therapy-related malignancies following treatment of germ cell cancer. 1059 12

It is known that alkylating agents and topoisomerase II inhibitors can cause distinct forms of therapy-related leukemia and myelodysplastic syndrome (TRL/MDS). Although several reports have been made on each of these agents separately, no study has yet been conducted to evaluate the effect of these two types of agents in the same population. In a nationwide, large-scale population study, the clinical and cytogenetic features as well as the prognostic factors in 256 patients with TRL/MDS were assessed. Median age was 61 years, and the median period of latency from primary malignancies was 47.9 months. The latency period was significantly shorter in patients undergoing chemotherapy, especially that of topoisomerase II inhibitors, for primary cancer. The morphological diagnosis of TRL/MDS was acute myeloid leukemia in 59% and MDS in 41% of patients. Chromosome abnormalities that frequently involved chromosomes 5, 7 or 11 were documented in 77% of the 189 patients examined. MLL gene rearrangements were detected in 11 of 58 subjects and were correlated with a borderline significance (P = 0.072) with topoisomerase II inhibitor administration. Overall median survival was only 9.7 months. Survival was similar in cases with or without MLL gene rearrangement. Multivariate analysis identified chromosome 5 abnormalities, hypoproteinemia, poor therapy outcomes for primary cancer, C-reactive protein, and thrombocytopenia as being significantly poor prognostic factors (P < 0.05). This large-population study provided a comprehensive update of TRL/MDS status in Japan, identified significant prognostic factors, and enabled the clinical significance of MLL gene rearrangement to be assessed.
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PMID:Therapy-related leukemia and myelodysplastic syndrome: a large-scale Japanese study of clinical and cytogenetic features as well as prognostic factors. 1074 24

Gene CBP codes for a transcriptional coactivator, which can interact with many transcriptional factors. It modifies the process of transcription stimulated by these factors by specific binding to RNA polymerase II holoenzyme or by histone acetylation. CBP gene mutation is the molecular cause of autosomal dominant genetic disease called Rubinstein-Taybi syndrome that is manifested by mental and growth retardations, by typical face malformations and broad thumbs and broad big toes. The CBP gene can be affected by the t(8;16)(p11;p13.3) translocation resulting in production of the MOZ/CBP chimeric protein and in induction of acute myeloblastic leukaemia. Therapy using topoisomerase II inhibitors can induce the t(11;16)(q23;13.3) translocation causing acute myeloid or lymphoid leukaemia or myelodysplasia through production of the MLL/CBP protein chimera.
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PMID:[Clinical sequelae of mutation of the CBP gene]. 1074 38


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