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)

Activated protein C resistance (APCR), usually due to the Arg506-->Gln point mutation of the factor V gene, has emerged as the most important hereditary cause of venous thromboembolism. Using an aPTT based method in the presence of APC, together with a DNA technique based on the polymerase chain reaction, we investigated 65 leukaemic children and 65 age-matched healthy controls for the presence of this mutation. In both groups three children showed APCR. All six children showed the common factor V gene mutation, Arg506-->Gln. Although no child in the control group presented with thrombosis, all three children with acute lymphoblastic leukaemia had thromboembolic events. Whether the poor anticoagulant response to activated protein C in leukaemic children treated with prednisone, vincristine, daunorubicin and asparaginase affects the risk of thrombotic events requires a more extensive multicentre study.
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PMID:Resistance to activated protein C (APCR) in children with acute lymphoblastic leukaemia--the need for a prospective multicentre study. 882 28

By selective depletion of CD4 and CD8 T cells in vivo using the respective mAbs, we demonstrate that CD4 T cells are necessary for skin graft rejection against thymus leukemia (TL) Ag. The skin expressing T3b-TL Ag from transgenic C3H Tg.Con.3-1 mice given chimeric H-2Kb/T3b-TL gene was rejected when grafted onto C3H/He recipient mice. Depletion of CD4, but not of CD8, T cells blocked rejection. CD8 CTL were generated in MEM (control)-treated C3H/He recipient mice, while Thy-1+ CD4- CD8- CTL were generated in CD8-depleted recipient mice after rejection. However, no CTL were generated in CD4-depleted or both CD4- and CD8-depleted recipient mice. Thus, the generation of both CD8 and Thy-1+ CD4- CD8- CTL was dependent on CD4 T cells. Ab blocking indicated that both CD8 and Thy-1+ CD4- CD8- CTL were TCR alphabeta and recognized TL Ag. We furthermore demonstrated that CD4 T cells in spleen cells from C3H/He mice that had rejected C3H Tg.Con.3-1 skin showed a weak, but significant, proliferative response to in vitro stimulation with mitomycin C-treated C3H Tg.Con.3-1 spleen cells. Analysis of the reactivity of bulk CD4 T cell lines to 73 synthetic overlapping peptides encompassing the entire T3b-TL molecule showed that CD4 T cells recognized multiple epitopes on the T3b-TL molecule in an APC-dependent manner.
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PMID:Requirement of CD4 T cells for skin graft rejection against thymus leukemia (TL) antigen and multiple epitopes on the TL molecule recognized by CD4 T cells. 920 Apr 51

A 66-year-old woman suffering from fever and thrombophlebitis was referred to our hospital. A peripheral blood examination revealed hyperleukocytosis with 96% blast cells and thrombocytopenia. The patient was diagnosed as having acute myeloid leukemia (AML) accompanied by disseminated intravascular coagulation (DIC). A marked decrease in protein C (PC) antigen and activity were observed. In this case, PC levels were lower than those observed in AML with DIC. Induction therapy for leukemia and treatment of DIC were started on the first day of hospitalization. The patient achieved complete remission, with PC antigen and activity levels normalized.
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PMID:Acute myeloid leukemia accompanied by multiple thrombophlebitis. 926 Jul 81

This article reviews the clinical pharmacokinetics of a water-soluble analogue of camptothecin, irinotecan [CPT-11 or 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy-camptoth eci n]. Irinotecan, and its more potent metabolite SN-38 (7- ethyl-10-hydroxy-camptothecin), interfere with mammalian DNA topoisomerase I and cancer cell death appears to result from DNA strand breaks caused by the formation of cleavable complexes. The main clinical adverse effects of irinotecan therapy are neutropenia and diarrhoea. Irinotecan has shown activity in leukaemia, lymphoma and the following cancer sites: colorectum, lung, ovary, cervix, pancreas, stomach and breast. Following the intravenous administration of irinotecan at 100 to 350 mg/m2, mean maximum irinotecan plasma concentrations are within the 1 to 10 mg/L range. Plasma concentrations can be described using a 2- or 3-compartment model with a mean terminal half-life ranging from 5 to 27 hours. The volume of distribution at steady-state (Vss) ranges from 136 to 255 L/m2, and the total body clearance is 8 to 21 L/h/m2. Irinotecan is 65% bound to plasma proteins. The areas under the plasma concentration-time curve (AUC) of both irinotecan and SN-38 increase proportionally to the administered dose, although interpatient variability is important. SN-38 levels achieved in humans are about 100-fold lower than corresponding irinotecan concentrations, but these concentrations are potentially important as SN-38 is 100- to 1000-fold more cytotoxic than the parent compound. SN-38 is 95% bound to plasma proteins. Maximum concentrations of SN-38 are reached about 1 hour after the beginning of a short intravenous infusion. SN-38 plasma decay follows closely that of the parent compound with an apparent terminal half-life ranging from 6 to 30 hours. In human plasma at equilibrium, the irinotecan lactone form accounts for 25 to 30% of the total and SN-38 lactone for 50 to 64%. Irinotecan is extensively metabolised in the liver. The bipiperidinocarbonylxy group of irinotecan is first removed by hydrolysis to yield the corresponding carboxylic acid and SN-38 by carboxyesterase. SN-38 can be converted into SN-38 glucuronide by hepatic UDP-glucuronyltransferase. Another recently identified metabolite is 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camptothecin (APC). This metabolite is a weak inhibitor of KB cell growth and a poor inducer of topoisomerase I DNA-cleavable complexes (100-fold less potent than SN-38). Numerous other unidentified metabolites have been detected in bile and urine. The mean 24-hour irinotecan urinary excretion represents 17 to 25% of the administered dose. Recovery of SN-38 and its glucuronide in urine is low and represents 1 to 3% of the irinotecan dose. Cumulative biliary excretion is 25% for irinotecan, 2% for SN-38 glucuronide and about 1% for SN-38. The pharmacokinetics of irinotecan and SN-38 are not influenced by prior exposure to the parent drug. The AUC of irinotecan and SN-38 correlate significantly with leuco-neutropenia and sometimes with the intensity of diarrhoea. Certain hepatic function parameters have been correlated negatively with irinotecan total body clearance. It was noted that most tumour responses were observed at the highest doses administered in phase I trials, which indicates a dose-response relationship with this drug. In the future, these pharmacokinetic-pharmacodynamic relationships will undoubtedly prove useful in minimising the toxicity and maximise the likelihood of tumour response in patients.
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PMID:Clinical pharmacokinetics of irinotecan. 934 1

Twelve dogs suffering from acute lymphoblastic leukaemia were investigated concerning the following tests: platelet count, prothrombin time (PT, standard test, modified test), activated partial thromboplastin time (APTT), activity of the individual coagulation factors II, V, VII, X, VIII:C, IX, XI, XII, prekallikrein, and high-molecular weight kininogen, the activity of antithrombin III (AT III), protein C, plasminogen, and alpha 2-antiplasmin as well as concentration of fibrinogen, soluble fibrin and fibrin(ogen) degradation products (FDP). All patients showed a decreased platelet count due to suppression of megakaryopoesis by infiltration of the bone marrow with leukaemic cells. In addition, in most of the patients a moderate activity decrease of one or more individual coagulation factors has been found, especially regarding factor II (median, x0.50 = 51%, p = 0.0001), but also factors X (x0.50 = 71%, p = 0.0003) and XI (x0.50 = 68%, p = 0.0006). This was reflected by the APTT and the PT activity (modified test), which were prolonged or decreased, respectively, in the majority of the cases. Furthermore, the activity of AT III and of plasminogen was distinctly diminished (p < 0.001). Like the concentration of FDP, the plasma level of soluble fibrin was significantly higher than in normal dogs (p < 0.001). This indicates that besides thrombocytopenia disseminated intravascular coagulation occurs frequently in dogs with acute lymphoblastic leukaemia and is a main cause for the decreased activity of several plasmatic components of the haemostatic system. The lack of correlation between the concentration of soluble fibrin as an indicator of intravascular coagulation and the total blast cell count (rS = 0.011) shows the importance of other factors like degree of cell lysis as well as participation of organs such as the liver for generation of consumption coagulopathy in dogs with acute lymphoblastic leukaemia.
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PMID:[Changes in hemostasis of dogs with acute lymphoblastic leukemia]. 951 98

To examine possible interference patterns between immunodominant CTL Ags, we analyzed the response to mixtures of five well-characterized H-2Kb-restricted epitopes, each of which had earlier been described as immunodominant within its antigenic system. Clear patterns of dominance were observed between peptides in the mixture, with the CTL response focusing on the Sendai virus nucleoprotein 324-332 and vesicular stomatitis virus nucleoprotein 52-59 epitopes. The dominance of these epitopes correlated with high CTL availability. Subdominance of the OVA(257-264) and the MCF1233 murine leukemia virus envelope 574-581 peptides could not be explained by inferior ability to bind and stabilize MHC class I molecules. Interestingly, immunodominance was broken if the peptide mixture was pulsed on bone marrow-derived dendritic cells, a mode of immunization allowing efficient recognition of a broader set of specificities. Our results show that immunodominance is neither an absolute feature of a given epitope nor does it apply only in relation to other epitopes within the same protein, micro-organism, or cell. Novel "superdominant" hierarchies emerge in the response against multiple "dominant" epitopes. A T cell competition model to explain the data in terms of a balance influenced by CTL frequencies and available APC capacity is discussed.
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PMID:Superdominance among immunodominant H-2Kb-restricted epitopes and reversal by dendritic cell-mediated antigen delivery. 953 Dec 71

Acute leukemia may be linked to disturbances of the coagulation system, which are usually due to hyperviscosity because of disseminated intravascular coagulation or a high white cell count. We report a unique case of femoral artery thrombosis as the beginning symptom of acute monocytic leukemia (M5) associated with a low level of functional protein C. The patient had multiple recurrent episodes of thrombosis with low levels of functional protein C associated with the relapse of the leukemia. A review of the literature shows that this is an extremely rare phenomenon.
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PMID:Acute femoral artery thrombosis associated with functional protein C deficiency as the presenting manifestation of acute monocytic leukemia. 967 39

We have previously reported high levels of the coagulation inhibitor TFPI in the blood of patients with gastrointestinal cancer. TFPI is not an acute-phase reactant, but high levels have also been reported in patients with septicaemia and disseminated intravascular coagulation (DIC). To study its relationship with other types of malignancy, TFPI activity was first determined in plasma samples from 214 patients with various malignancies. In a second cohort of 83 patients, total and free TFPI antigen, protein C, antithrombin, fibrin monomer and D-dimer were also measured. Elevated TFPI activity and antigens were found in about half of the patients with solid tumours. In contrast, elevated TFPI was rare in haematological malignancies (12%). In the 18 patients with acute nonlymphocytic leukaemia (ANLL), elevated free TFPI was found only in patients who also had DIC. No correlation was found between TFPI levels and fibrin monomer or D-dimer levels. Only four out of 20 patients with solid tumours had normal levels of fibrin monomer and D-dimer, yet three out of these four had elevated TFPI. In conclusion, elevated TFPI in ANLL is related to the coexistence of DIC. In solid tumour disease increased TFPI may reduce protective fibrin formation, but the pathogenic mechanism is as yet unknown.
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PMID:Elevated TFPI in malignant disease: relation to cancer type and hypercoagulation. 973 35

The etiology of thrombo-embolic events after therapy with asparaginase (ASP) is not fully understood. To investigate if cytotoxic drugs given in combination with asparaginase (ASP) have an additional effect on the coagulation system, a detailed analysis of coagulation factors was performed. Therefore, we investigated two combinations of the COALL-05-92-protocol, [cylophosphamide]/methotrexate/ASP ([CYC]/MTX/ASP) and high dose arabinoside/ASP (HIDAC/ASP). In 33 children with acute lymphoblastic leukaemia the following parameters were determined: plasminogen-activator-inhibitor-1, plasminogen, antiplasmin, protein C, antithrombin, modified antithrombin, prothrombin-fragments 1 + 2 and thrombinantithrombin-complex. All children had an indwelling catheter. The most distinctive result of this investigation is that plasminogen shows a deeper and longer lasting decrease in the [CYC]/MTX/ASP-combination (median 65% NHP) compared to the HIDAC/ASP-combination (median 105% NHP) (p = 0.01). The other parameters showed the characteristic changes after ASP-therapy. None of our patients developed any clinical signs of thrombosis, even though two patients showed four altered coagulation parameters on the same day. This shows, that the coexistence of indwelling catheters plus four decreased coagulation parameters does not necessarily imply the development of thrombosis. We conclude that the parameters measured in this study do not sufficiently predict the development of thrombosis.
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PMID:Coagulation and fibrinolysis in children with acute lymphoblastic leukaemia treated according to the COALL-05-92-protocol. 974 67

Owing to the high efficacy of L-asparaginase in the treatment of acute lymphatic leukaemia the enzyme was introduced into the chemotherapy schedules for remission induction of this disease shortly after results of large-scale clinical trials had become available. Since asparaginase monotherapy was associated with a high response rate but short remission duration, the enzyme is currently employed within the framework of combination chemotherapy schedules which achieve treatment response in about 90% and long-term remissions in the majority of patients. Recently initiated clinical trials have still confirmed the eminent value of asparaginase in the combination chemotherapy of acute lymphatic leukaemia and of some subtypes of non-Hodgkin lymphoma, and its important role as an essential component of multimodal treatment protocols. Despite the unique mechanism of action of this cytotoxic substance which shows relative selectivity with regard to the metabolism of malignant cells, some patients experience toxic effects during asparaginase therapy. Immunological reactions toward the foreign protein include enzyme inactivation without any clinical manifestations as well as anaphylactic shock. Severe functional disorders of organ systems result from the impaired homeostasis of the amino acids asparagine and glutamine. The changes affecting the proteins of the coagulation system have considerable clinical impact as they may induce bleeding as well as thromboembolic events and may be associated with life-threatening complications when the central nervous system is involved. Risk factors predisposing to thromboembolic complications are hereditary resistance against activated protein C and any other hereditary thrombophilia. Other organ systems potentially affected by relevant functional disorders are the central nervous system, the liver, and the pancreas, with patients who have a history of pancreatic disorders carrying an especially high risk of developing pancreatitis. Studies on the mechanisms of action and the occurrence of resistance phenomena have shown that a treatment response may only be expected if the malignant cells are unable to increase their asparagine synthetase activity to an extent providing enough asparagine to the cell; one may thus conclude that the enzyme-induced asparagine depletion of the serum constitutes the decisive cytotoxic mechanism. Independent of the asparagine depletion related cytotoxicity however, there are other mechanisms of clinical relevance like induction of apoptosis. Besides this, further influences on signal transduction cannot be excluded. Only few publications have dealt with the question of minimum trough activities to be ensured before each subsequent asparaginase dose in order to maintain uninterrupted asparagine depletion under treatment, and answers to this problem are not definitive. Clinical studies using enzymes from E. coli strains indicate that a trough activity of 100 U/l will suffice for complete asparagine depletion of the fluid body compartments with the preparations studied. These findings have been transferred to enzymes from other E. coli strains as well as those isolated from Erwinia chrysanthemi and to the PEG-conjugated E. coli asparaginases. It might be desirable to countercheck the results for confirmation or correction. The dosage and administration schedule of the various enzyme preparations required for complete asparagine depletion over a period of time have been insufficiently defined. While pharmacokinetic studies showed clinically relevant differences in biological activity and activity half-lives for enzymes from different biological sources, the findings of recently published clinical trials indicate that the therapeutic efficacy is affected when different asparaginase preparations are given by identical therapy schedules. (ABSTRACT TRUNCATED)
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PMID:Use of L-asparaginase in childhood ALL. 976 45


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