Summ_uxy A point mutation in the mRNA of NADP(H): quinone oxidoreductase 1 (NQOI, DT-diaphorase) is believed to be responsible for reduced enzyme activity in the adenocarcinoma BE cell line. The
A polymorphism in NAD(P)H:quinone oxidoreductase (NQO1): relationship of a homozygous mutation at position 609 of the NQO1 cDNA to NQO1 activity Sir -NQO1 has attracted considerable attention owing to its ability to deactivate a broad range of xenobiotics while activating certain anti-tumour quinones (Ross et al., 1994). A number of recent reports have highlighted the occurrence and potential significance of a point mutation in the NQO1 gene which is associated with a loss of NQO1 activity in both normal and tumour tissue (Traver et al., 1992; Eickelmann et al., 1994a,b;Rosvold et al., 1995;Kolesar et al., 1995). The mutation is a C to T point mutation at position 609 of the NQO1 cDNA which codes for a proline to serine substitution in the amino acid sequence of the protein (Traver et al., 1992). The mutation was originally characterised in the BE human colon adenocarcinoma cell line by SSCP analysis and sequencing (Traver et al., 1992) and subsequently in the H596 human non-small-cell lung cancer cell line by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique (1995) have recently examined the relationship between the heterozygous mutation at position 609 and NQO1 activity. These data demonstrate a wide range of NQO1 activity in IC to T heterozygotes and suggests a significant role for post-transcriptional modification in determination of NQO1 activity.In the paper by Kuehl et al. (1995), the BE cell line is described as heterozygous for the 9C-T point mutation with very low NQO1 activity. An additional fibroblastoid cell line, the 3701T line, was reported as homozygous for the mutation with very low NQO1 activity. Since these results differed, with respect to the BE cell line, from the original report of Traver et al. (1992) al., 1995). Because of the somewhat nonspecific nature of both DCPIP as a substrate and dicoumarol as an inhibitor (Ross et al., 1993), it is possible that the extremely low rates of dicoumarol-inhibitable DCPIP reduction obtained in BE, H596 or 3701T cells may reflect the presence of reductases other than NQO1. Our joint findings confirm previous results that the BE cells are homozygous for the 609C-T mutation and that the presence of the homozygous mutation is associated with a loss of NQO1 protein activity (Traver et al., 1992. The same conclusion was reached by Eickelmann et al. (1994) who reported that a cell line and three human kidney carcinoma samples without detectable NQO1 activity were all homozygous for the IC to T mutation.An alternatively spliced form of NQO1 lacking exon 4 and the quinone binding site has recently been reported (Gasdaska et al., 1995). This form of NQO1 has minimal enzyme activity with traditional model substrates for NQO1 but retains immunoreactivity and can be detected using a polyclonal antibody to NQO1 (Gasdaska et al., 1995). We have also examined BE and H596 cells for NQO1 protein using the same polyclonal antibody used by Gasdaska and colleagues and were unable to detect NQO1 protein. We have recently sugg...
Patients with cancer are at increased risk of venous thromboembolism (vte). Anticoagulation therapy is used to treat vte; however, patients with cancer have unique clinical circumstances that can often make decisions surrounding the administration of therapeutic anticoagulation complicated. No national Canadian guidelines on the management of established cancer-associated thrombosis have been published. We therefore aimed to develop a consensus-based, evidence-informed guideline on the topic.PubMed was searched for clinical trials and meta-analyses published between 2002 and 2013. Reference lists of key articles were hand-searched for additional publications. Content experts from across Canada were assembled to review the evidence and make recommendations.Low molecular weight heparin is the treatment of choice for cancer patients with established vte. Direct oral anticoagulants are not recommended for the treatment of vte at this time. Specific clinical scenarios, including the presence of an indwelling venous catheter, renal insufficiency, and thrombocytopenia, warrant modifications in the therapeutic administration of anticoagulation therapy. Patients with recurrent vte should receive extended (>3 months) anticoagulant therapy. Incidental vte should generally be treated in the same manner as symptomatic vte. There is no evidence to support the monitoring of anti–factor Xa levels in clinically stable cancer patients receiving prophylactic anticoagulation; however, levels of anti–factor Xa could be checked at baseline and periodically thereafter in patients with renal insufficiency. Follow-up and education about the signs and symptoms of vte are important components of ongoing patient care.
Patients with cancer are at increased risk of venous thromboembolism (vte). Anticoagulation therapy has been shown to prevent vte; however, unique clinical circumstances in patients with cancer can often complicate the decisions surrounding the administration of prophylactic anticoagulation. No national Canadian guidelines on the prevention of cancer-associated thrombosis have been published. We therefore aimed to develop a consensus-based, evidence-informed guideline on the topic.PubMed was searched for clinical trials and meta-analyses published between 2002 and 2013. Reference lists of key articles were hand-searched for additional publications. Content experts from across Canada were assembled to review the evidence and make recommendations.Low molecular weight heparin can be used prophylactically in cancer patients at high risk of developing vte. Direct oral anticoagulants are not recommended for vte prophylaxis at this time. Specific clinical scenarios, including renal insufficiency, thrombocytopenia, liver disease, and obesity can warrant modifications in the administration of prophylactic anticoagulant therapy. There is no evidence to support the monitoring of anti–factor Xa levels in clinically stable cancer patients receiving prophylactic anticoagulation; however, factor Xa levels could be checked at baseline and periodically in patients with renal insufficiency. The use of anticoagulation therapy to prolong survival in cancer patients without the presence of risk factors for vte is not recommended.
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