UMLS:C0026986 - FACTA Search

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)

This report describes the efficacy and toxicity of PAVe (procarbazine, Alkeran, vinblastine) and irradiation (RT) in the management of 159 patients with locally extensive or advanced stage Hodgkin's disease (HD) at Stanford University. Patients received six courses of chemotherapy alternating with RT. The extent of RT and the schedule of treatment varied according to the stage of disease. About 2/3 of patients received PAVe/RT in the setting of prospective, randomized clinical trials. The rate of complete response was 93%. With a median follow-up of seven years (range 2-17), the 15 year actuarial freedom from progression (FFP) is 78% and overall survival is 75%. Ten-year FFP by stage is: 80% for locally extensive stage II, 90% for stage IIIA and 70% for stage IIIB. Excellent and equal results were attained with PAVe/RT vs. MOP(P) (mustard, Oncovin, procarbazine with or without prednisone)/RT in the randomized combined modality studies. Progression or recurrence was documented in 30 patients and was more common in irradiated sites. PAVe was well tolerated acutely. There were no treatment related fatalities. Twenty-three (14%) patients were admitted to the hospital for neutropenic fever. Five second malignancies have occurred after PAVe/RT only: one myelodysplastic syndrome, one acute myelogenous leukemia, one non-Hodgkin's lymphoma and two solid tumors including a case of non-small cell lung cancer and an in situ carcinoma of the cervix. Three patients died from myocardial infarction several years after the completion of treatment. These mature data show that PAVe/RT is effective and well-tolerated therapy for locally extensive stage II and IIIA/B HD.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The Stanford experience with combined procarbazine, Alkeran and vinblastine (PAVe) and radiotherapy for locally extensive and advanced stage Hodgkin's disease. 145 64

Since there have been relatively high incidence of cancer of the digestive organs in Japan, many 5-fluorouracil analogues have been studied as the drugs to treat such cancers. Beside these fluoropyrimine compounds, cytosine arabinoside (ara-C) analogues have also been studied, and some of them have shown appreciable clinical activities against human malignancies. In this paper, as such analogues, experimental and clinical studies of gemcitabine (dFdC). DMDC and cytarabine ocfosfate were reviewed. Among these drugs, gemcitabine (Eli Lilly, Japan) showed more than 20% response rate against non-small cell lung cancer in the late phase II study in Japan. Unfortunately, clinical study of DMDC (Yoshitomi) is currently suspended because of the lack of the hint of clinical activity, but the author believes that this might show some clinical activities by changing the treatment regimens in the future. Cytarabine ocfosfate (Nippon Kayaku) has already put on market as the first drug to be active against ANLL and MDS by giving orally.
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PMID:[Recent development of antitumor antimetabolites in Japan--cytosine arabinoside analogues]. 917 May 12

Amifostine (WR-2721, Ethyol), S-2[3-aminopropylamino]-ethyl-phosphorothioic acid, was selected as a clinically usable radioprotector from more than 4,400 compounds in the 1950s. A considerable amount of preclinical work suggested that amifostine, or its activated thiol WR-1065, protected normal cells effectively against the adverse effects of irradiation and several anticancer drugs without exhibiting tumor protection. In non-randomized and randomized trials in malignant melanoma, colorectal cancer, head and neck cancer, non-small cell lung cancer, and epithelial ovarian carcinoma, amifostine significantly reduced the hematological and non-hematological toxicity of DNA-damaging agents such as alkylators, platinum compounds, or mitomycin C. In more recent studies, the drug also protected patients from side effects produced by taxanes or topoisomerase I inhibitors and is thus likely to allow higher cytostatic doses to be administered. Currently, there is no evidence that amifostine compromises the antineoplastic effect of the drugs studied. Otherwise, W/R-2721 may even improve the therapeutic efficacy of agents like cisplatin, carboplatin, or paclitaxel. Moreover, amifostine appears to produce growth-factor like properties resulting in growth-promoting effects on primitive blood progenitor cells ex vivo. Amifostine offers a rational approach to protect patients against chemotherapy-specific and often dose-limiting effects and is thus likely to improve therapeutic outcome significantly. Future studies should be focused on both new indications like childhood cancer, myelodysplastic syndromes, dose-intensified or high- dose chemotherapy, and multimodality approaches and optimization of amifostine dosage in order to reduce dose-limiting side effects. Then, the drug may play a major role in more specific and individualized oncologic strategies.
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PMID:Chemoprotection in anticancer therapy: the emerging role of amifostine (WR-2721). 970 84

The CCAAT/enhancer binding protein alpha (C/EBPalpha) protein is essential for proper lung and liver function and granulocytic and adipose tissue differentation. It was hypothesized that abnormalties in C/EBPalpha function contribute to the development of malignancies in a variety of tissues. To test this, genomic DNA from 408 patient samples and 5 cell lines representing 11 different cancers was screened for mutations in the C/EBPalpha gene. Two silent polymorphisms termed P1 and P2 were present at frequencies of 13.5% and 2.2%, respectively. Of the 12 mutations detected in 10 patients, silent changes were identified in one nonsmall cell lung cancer, one prostate cancer, and one acute myelogenous leukemia (AML) subtype M4. The 9 remaining mutations were detected in 1 of 92 (1.1%) myelodysplastic syndrome (MDS) samples and 6 of 78 (7.7%) AML (AML-M2 and AML-M4) samples. Some mutations truncated the predicted protein with loss of the DNA-binding (basic region) and dimerization (leucine zipper [ZIP]) domains by either deletions or nonsense codons. Also, inframe deletions or insertions in the fork region located between the leucine zipper and basic region, or within the leucine zipper, disrupted the alpha-helical phase of the bZIP domain. The inframe deletion and insertion mutations abrogated the transcriptional activation function of C/EBPalpha on the granulocyte colony-stimulating factor receptor promoter. These mutants localized properly to the nucleus, but were unable to bind to the C/EBP site in the promoter and did not possess dominant-negative activity. The mutations in the MDS patient and one AML-M2 patient were biallelic, indicating a loss of C/EBPalpha function. These results suggest that mutation of C/EBPalpha is involved in specific subtypes of AML and in MDS, but may occur rarely in other types of leukemias or nonhematologic malignancies.
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PMID:Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. 1183 Apr 84

Decitabine [NSC 127716, DAC, dezocitidine, Aza dC, 2'-deoxy-5-azacytidine] is a deoxycytidine and cytarabine derivative with potent antileukaemic activity, which was originated by Pharmachemie. This antimetabolite is able to induce in vitro gene activation and cellular differentiation by a mechanism involving DNA hypomethylation. SuperGen acquired worldwide rights to decitabine from Pharmachemie in the third quarter of 1999 for 4 million US dollars worth of SuperGen shares and income from manufacture upon the launch of decitabine. SuperGen announced in May 2000 that it had entered a Cooperative Research and Development Agreement (CRADA) with the US National Cancer Institute (NCI). SuperGen will supply decitabine to the NCI, which will initiate and sponsor clinical trials in patients with solid tumours and haematological malignancies. The NCI will also conduct studies on decitabine's mechanism of action. In 2002, the US FDA has granted decitabine orphan drug status for the treatment of myelodysplastic syndromes and sickle cell anaemia. In February 2003, the European Commission granted orphan drug status to decitabine for myelodysplastic syndrome. Decitabine has also received orphan drug status in the US as a host-protective agent in the treatment of AML. Decitabine has been studied in solid tumours as well as in different types of leukaemia. In several phase II studies it has been shown to have very limited efficacy against solid tumours. However, decitabine has shown better activity in the treatment of haematological malignancies such as acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML) and myelodysplastic syndrome (preleukaemia). In March 2001, SuperGen announced that it had begun patient enrolment into its pivotal open-label phase III trial of decitabine in advanced myelodysplastic syndrome patients. The study, which will compare decitabine with standard care therapy, will be conducted at 15 medical centres in the US and will enrol a total of 160 patients. In March 2003, SuperGen announced that patient enrolment was complete. The study, which will compare decitabine with standard care therapy, will be conducted at 22 medical centres in the US and will enrol a total of 160 patients. A European pivotal trial is also underway for the same indication, and is aiming to enrol 220 patients. A phase I/II trial of 8 patients, designed to establish safety and efficacy in the treatment of sickle cell anaemia, has been completed at the University of Illinois, USA. Plans for additional studies of decitabine as a treatment for sickle cell anaemia are underway. Decitabine is also undergoing phase II clinical trials in Canada, for the treatment of non-small cell lung cancer, and in the US for chronic myeloid leukaemia and prostate cancer. Glasgow University in Scotland has conducted preclinical trials in chemotherapy-resistant ovarian and colon cancers. The results suggest that decitabine administration may reverse chemotherapy resistance in these cancers. SuperGen was issued a US patent (No. 6 191 119) in 2001 covering the use of decitabine in combination with rubitecan and antibiotic agents, including doxorubicin.
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PMID:Decitabine: 2'-deoxy-5-azacytidine, Aza dC, DAC, dezocitidine, NSC 127716. 1275 5

Decitabine [NSC 127716, DAC, dezocitidine, Aza dC, 2'-deoxy-5-azacytidine, Dacogen( trade mark )] is a deoxycytidine and cytarabine derivative with potent antileukaemic activity, originated by Pharmachemie. This antimetabolite is able to induce in vitro gene activation and cellular differentiation by a mechanism involving DNA hypomethylation. Decitabine has been studied in several phase II trials for solid tumours as well as in different types of leukaemia. The drug has been shown to have very limited efficacy against solid tumours. However, decitabine exhibits higher activity for the treatment of haematological malignancies. SuperGen announced that it had entered a Cooperative Research and Development Agreement (CRADA) with the US National Cancer Institute (NCI) in May 2000. SuperGen will supply decitabine to the NCI, which will initiate and sponsor clinical trials in patients with solid tumours and haematological malignancies. The NCI will also conduct studies on decitabine's mechanism of action. SuperGen had previously acquired worldwide rights to decitabine from Pharmachemie in the third quarter of 1999 for 4 million US dollars worth of SuperGen shares and income from manufacture upon the launch of decitabine. The drug is undergoing two phase II trials for the treatment of cytomegalovirus leukaemia (CML) in the US, one of which will assess the safety, response rate, duration of response, and survival of decitabine (injection) in combination with imatinib mesylate (oral). SuperGen initiated a phase II clinical study of decitabine in combination with imatinib mesylate in June 2003 that will be conducted under SuperGen's CRADA with the National Cancer Institute and will take place at the MD Anderson Cancer Center in the US. Approximately 80 patients with CML will be enrolled in the study. This followed on decitabine's orphan drug status for the same indication, which was granted by the US FDA in 2002. In addition, the European Commission has granted orphan drug status to decitabine for MDS treatment in February 2003. In March 2003, SuperGen announced that patient enrolment was completed for its open-label, phase III trial comparing decitabine with standard care therapy for treatment of advanced myelodysplastic syndrome, which was initiated in March 2001. The study will be conducted at 22 medical centres in the US and will enrol a total of 160 patients. A pivotal trial is also underway in Europe for the same indication and is aiming to enrol 220 patients. In addition, decitabine is undergoing phase II trials for the treatment of non-small cell lung cancer (NSCLC) in Canada and for prostate cancer in the US. In July 2003, SuperGen was issued a US patent relating to decitabine as part of a combination therapy with other anticancer agents to treat ovarian, breast, prostate, gastric, lung, pancreatic and colon cancers through the correction of DNA hypermethylation. SuperGen was issued a US patent (No. 6 191 119) in 2001 covering the use of decitabine in combination with rubitecan and antibiotic agents, including doxorubicin.
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PMID:Decitabine: 2'-deoxy-5-azacytidine, Aza dC, DAC, dezocitidine, NSC 127716. 1458 64

The farnesyltransferase inhibitors (FTIs) were designed to inhibit the post-translational processing of Ras proteins, which are mutated in 30% of all human cancers. Recent studies suggest, however, that the target of FTIs may be a protein other than Ras, and that these agents may be more appropriately used to treat tumors with activated wild-type ras signaling. Preliminary results from several phase II and phase III studies have been reported. The FTIs fail to show significant single-agent activity in non-small cell lung cancer, small cell lung cancer, pancreatic cancer, refractory colorectal cancer, and bladder cancer. Activity has been shown in hematologic malignancies (acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome), breast cancer, and glioma. Several combination studies of FTIs and standard cytotoxic agents are ongoing.
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PMID:Farnesyltransferase inhibitors. 1498 78

Specific cytogenetic alterations in t-MDS and t-AML are associated with different chemotherapeutic agents, such as loss of chromosomal material from #5 and #7 with alkylators. No data have been published on secondary leukemias following the taxane docetaxel. We report a patient, who being in long-term remission after docetaxel-based induction chemotherapy with docetaxel and carboplatin, surgery and adjuvant radiotherapy for non-small cell lung cancer stage IIIB, developed a t-MDS and subsequently a t-AML 40 months after start of therapy. The t-MDS was characterised by a complex aberrant karyotype including monosomy #13 and partial monosomies of #5 and #7. This is the first report in the literature of t-MDS after docetaxel chemo-radiotherapy, implicating a possible association of docetaxel with alkylator type t-MDS and t-AML. The case will be discussed in the context of a review of the current literature.
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PMID:Secondary leukaemia after cure for locally advanced NSCLC: alkylating type secondary leukaemia after induction therapy with docetaxel and carboplatin for NSCLC IIIB. 1508 91

Topotecan (Hycamtin) is a water soluble semisynthetic analogue of the alkaloid camptothecin which has antitumour activity in preclinical models in vitro and in vivo. A range of Phase I studies has been performed and a daily x 5 iv. schedule, which showed most promising evidence of activity, was selected for extensive clinical evaluation. To date, topotecan has been shown to be active in a number of malignancies, including metastatic ovarian cancer, recurrent small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), breast cancer, colorectal cancer and myelodysplastic syndrome. In ovarian cancer, response rates of around 15% were identified in patients who had failed standard chemotherapy, and in a randomised, comparative study with paclitaxel response rates of 20% (topotecan) and 13% (paclitaxel) were observed. In addition, overall time to progression was impressive at 23 weeks (topotecan) compared with 14 weeks (paclitaxel). In recurrent SCLC, topotecan has shown good activity in sensitive patients with a response rate of 39%, although the response rate in refractory patients was considerably lower (7%). Median survival of all patients was 5.4 months, acceptable for this difficult clinical scenario. Topotecan is well-tolerated in the majority of patients and subjective toxicities are uncommon. The principal side-effect is myelosuppression, mainly neutropenia. Serious clinical sequelae are relatively uncommon and non-cumulative. Nonhaematological toxicities are generally mild and not dose-limiting. In clinical use, topotecan has exhibited activity in multiple tumour types, with a side-effect profile that is predictable and manageable. The drug is under evaluation in other tumour types and in combination chemotherapy regimens.
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PMID:Topotecan, an active new antineoplastic agent: review and current status. 1598 23

Epigenetic events, such as aberrant DNA methylation, have been demonstrated to silence the expression of many genes that suppress malignancy. Since the event is reversible, it is an interesting target for intervention with specific inhibitors of DNA methylation, such as 5-aza-2'-deoxycytidine (5-AZA-CdR, decitabine). 5-AZA-CdR is a prodrug that requires activation via phosphorylation by deoxcytidine kinase. The nucleotide analog is incorporated into DNA, where it produces an irreversible inactivation of DNA methyltransferase. 5-AZA-CdR is an S-phase-specific agent. The demethylation of DNA by this analog in neoplastic cells can lead to the reactivation of silent tumor-suppressor genes, induction of differentiation or senescence, growth inhibition, and loss of clonogenicity. 5-AZA-CdR was demonstrated to be a potent antineoplastic agent against leukemia and tumors in animal models. Preliminary clinical trials of 5-AZA-CdR using different dose-schedules have shown interesting antineoplastic activity in patients with leukemia, myelodysplastic syndrome (MDS), and non-small cell lung cancer (NSCLC). Pharmacokinetic studies have shown that 5-AZA-CdR has a short in vivo half-life of 15 to 25 minutes. The major toxicity produced by this analog is granulocytopenia. To exploit the full chemotherapeutic potential of 5-AZA-CdR for the treatment of cancer, its optimal dose-schedule has to be found. This will require a good understanding of the pharmacology of this analog and its action on both normal and neoplastic cells.
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PMID:Epigenetic therapy of cancer with 5-aza-2'-deoxycytidine (decitabine). 1621 84

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