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At least 19 recordsLinked to original sources
PubMed2000

Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies.

Most chemotherapeutic drugs can induce tumor cell death by apoptosis. Analysis of the molecular mechanisms that regulate apoptosis has indicated that anticancer agents simultaneously activate several pathways that either positively or negatively regulate the death process. The main pathway from specific damage induced by the drug to apoptosis involves activation of caspases in the cytosol by pro-apoptotic molecules such as cytochrome c released from the mitochondrial intermembrane space. At least in some cell types, anticancer drugs also upregulate the expression of death receptors and sensitize tumor cells to their cognate ligands. The Fas-mediated pathway could contribute to the early steps of drug-induced apoptosis while sensitization to the cytokine TRAIL could be used to amplify the response to cytotoxic drugs. The Bcl-2 family of proteins, that includes anti- and pro-apoptotic molecules, regulates cell sensitivity mainly at the mitochondrial level. Anticancer drugs modulate their expression (eg through p53-dependent gene transcription), their activity (eg by phosphorylating Bcl-2) and their subcellular localization (eg by inducing the translocation of specific BH3-only pro-apoptotic proteins). Very early after interacting with tumor cells, anticancer drugs also activate lipid-dependent signaling pathways that either increase or decrease cell ability to die by apoptosis. In addition, cytotoxic agents can activate protective pathways that involve activation of NFkappaB transcription factor, accumulation of heat shock proteins such as Hsp27 and activation of proteins involved in cell cycle regulation. This review discusses how modulation of the balance between noxious and protective signals that regulate drug-induced apoptosis could be used to improve the efficacy of current therapeutic regimens in hematological malignancies.

Antineoplastic Agents↗
PubMed2001

Application of Resistance Reversal Agents in Hematologic Malignancies; Malignancy; Current Clinical Practice.

The clinical application of resistance reversal drugs for patients with hematologic malignancies is reviewed. The phenomenon of multidrug resistance versus other mechanisms are discussed. The pump-like mechanisms of P-glycoprotein, multidrug resistance associated protein, lung resistance protein and of other ATP binding cassette transporter proteins are reviewed briefly, as well as the important substrate drugs and pump-blocking compounds. The problems associated with resistance protein assays in clinical samples and the concept of prognostic versus therapeutic clinical relevance are described, within the context of selected hematologic malignancies. Toxicities and treatment outcomes of phase II and III trials of reversal agents in lymphoma, multiple myeloma, myelodysplastic syndromes, acute myeloid leukemia and blast phase of chronic myeloid leukemia are reviewed. Finally, current options for on-study management of relapsed or refractory hematologic malignancy patients are discussed.

Journal Article↗
PubMed1989

Comparison of thrombolytic agents: selected hematologic, vascular and clinical events.

Plasminogen activators of distinct structure and biochemical action seem to be more equivalent than unique regarding induced blood changes and clinical complications. All of the activators ultimately degrade substrate through plasmin, resulting in a striking hypocoagulable state characterized primarily by a decrease in fibrinogen concentration. Infusion regimens are inversely proportional to the half-life of the activator, which is relatively long with anisoylated plasminogen streptokinase activator complex (APSAC), intermediate for streptokinase (SK) and urokinase (UK), and very short for recombinant tissue plasminogen activator (rt-PA) and recombinant single-chain urokinase plasminogen activator (scu-PA). After therapy is discontinued, hypofibrinogenemia persists until activator is cleared from the blood, then is slowly corrected over 48 hours, regardless of which thrombolytic agent has been used. Coagulation and platelet activity may be transiently accentuated soon after administration of the agent. Hypercoagulability contributes to vascular reocclusion, especially when acting in concert with the thrombogenic influences of residual thrombus and the original ruptured atherosclerotic plaque. In the first 3 to 4 hours after symptom onset, coronary artery reperfusion can be achieved with all of the thrombolytic agents in 50 to 60% of patients, with a greater thrombolytic potential of rt-PA over SK in thrombi of greater than 4 hours' duration. After coronary artery reperfusion, reocclusion occurs in 10 to 20% of patients, more often after rt-PA than SK treatment. Antiplatelet agents such as aspirin decrease the incidence of reocclusion and when added to either SK or rt-PA, decrease mortality after acute myocardial infarction by half. APSAC appears to have a maximal beneficial effect in reducing mortality even without aspirin.(ABSTRACT TRUNCATED AT 250 WORDS)

Fibrinolytic Agents↗
PubMed1976

[Infectious complications observed during the use of antimitotic agents in hematology].

During acute lymphoblastic leukemia in children, bacterial infections occur during initial treatment, whereas virus infections are observed during remission. Mycoses and pneumocystis carinii infections are the commonest late complications. During agranulocytosis, any prolonged fever should be considered as due to infection and probably septicemia. The bacteria are usually of digestive origin. Antibiotic therapy is only very inconstantly efficacious, and the course follows closely the number of granular cells, thus justifying the use of white cell transfusions.

Antineoplastic Agents↗
PubMed1999

Treatment of essential thrombocythemia with special emphasis on leukemogenic risk.

Acute leukemia and myelodysplastic syndromes are rare, but almost invariably fatal, evolutions of essential thrombocythemia (ET). Three major factors are associated with blastic transformation: cytogenetic abnormalities, myelofibrotic features, and the use of cytotoxic agents. Hematological malignancies have been reported in ET patients after treatment with alkylating agents, such as busulphan, as well as other cytoreductive drugs, such as hydroxyurea. Concerns about leukemogenicity have led some to suggest limiting the indications of these drugs to patients at higher risk of bleeding and thrombosis. Major risk factors for thrombosis are age above 60 years and a previous thrombotic event, whereas an increased bleeding tendency has been reported with platelet counts in excess of 1000-1500x10(9)/l. No myelosuppressive therapy is recommended for younger patients if they are asymptomatic or their platelet counts are below 1500x10(9)/l. The threshold of 1500x10(9)/l is controversial, however, and cytoreduction can be considered when platelets are above 1000x10(9)/l or in the presence of risk factors for cardiovascular disease. In the presence of thrombotic events or extreme thrombocytosis, young ET patients can be managed with cytoreductive agents theoretically devoid of leukemogenic risk, such as a-interferon or anagrelide. Nevertheless, the mutagenic risk of anagrelide has not been investigated in long-term follow-up studies, and the ultimate place of these 'new' drugs in the management of ET patients remains to be established in prospective and controlled clinical trials.

Antineoplastic Agents↗