Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-Fluorouracil (5-FU) administered in several schedules since its introduction in 1957 continues to be an integral part of standard first-line therapy for colorectal cancer. Continuous intravenous (i.v.) infusion appears to yield improved response rate and overall survival, with fewer adverse effects compared with i.v. bolus dosing. However, these protracted infusions require portable infusion pumps and central venous lines, which are associated with complications (i.e. increased risk of infection and clotting and/or dislodgement of the catheter, increased risk of venous thrombosis). Colorectal carcinoma is the second cause of death for tumour after lung cancer. About 70% of cases occur over 65 years and 50% or more affects people over 70. In clinical research age was a common exclusion criteria and little information is available about the efficacy, safety and toxicity of chemotherapy in elderly patients because few studies focused on the treatment of cancer in that part of population. The goal of this article is to review the literature concerning the treatment of elderly patients with UFT, an orally administered dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine.
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PMID:The role of uracil-tegafur (UFT) in elderly patients with colorectal cancer. 1536 68

5-Fluorouracil (5-FU) and its derivatives have been used worldwide for the treatment of several malignancies in solid organs. The effectiveness of these drugs is well proven in gastrointestinal malignancy, and has been reported upon the inverse correlation with the tumoral expression of dihydropyrimidine dehydrogenase (DPD). However, the significance of DPD expression in 5-FU based chemotherapy has not been well investigated in non-small cell lung cancer (NSCLC). We examined enzymatic activities and immunohistochemical expression of thymidylate synthase (TS) and DPD in 84 cases of NSCLC. In vitro sensitivity for 5-FU was tested in 53 cases of them to evaluate these predictive values for effectiveness of 5-FU. Efficacy of 5-chloro-2,4-dihydroxypyridine (CDHP), potent DPD inhibitor, was also examined in 27 cases of them. There was a reversal correlation between protein expression of DPD and sensitivity to 5-FU (r = -0.65; p < 0.001). Six (33.3%) of 18 cases with strong expression of DPD showed 10% or more increment of the anti-tumor effect by adding CDHP to 5-FU. DPD inhibitory fluoropyrimidine and examination of the tumoral expression of DPD might be a promising chemotherapeutic strategy in NSCLC.
Lung Cancer 2005 Jul
PMID:Role of dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine against non-small cell lung cancer--in correlation with the tumoral expression of thymidylate synthase and dihydropyrimidine dehydrogenase. 1594 89

The Cdc25 dual-specificity phosphatases are key regulators of cell cycle progression through activation of cyclin-dependent kinases (Cdk). Three homologs exist in humans: Cdc25A, Cdc25B, and Cdc25C. Cdc25A and Cdc25B have oncogenic properties and are overexpressed in some types of tumors. Compounds that inhibit Cdc25 dual-specificity phosphatase activity might thus be potent anticancer agents. We screened several hundred compounds in a library using an in vitro phosphatase assay, with colorimetric measurement of the conversion of p-nitrophenyl phosphate (pNPP) to p-nitrophenol by the catalytic domain of recombinant human Cdc25, and discovered TPY-835, which inhibits Cdc25A and Cdc25B activity (IC50 = 5.1 and 5.7 microM, respectively). TPY-835 had mixed inhibition kinetics for Cdc25A and Cdc25B. TPY-835 caused cell cycle arrest in the G1 phase in human lung cancer cells (A549 and SBC-5) but not cell cycle arrest in the G2/M phase. After treatment with TPY-835, the activation of Cdk2 was suppressed and phosphorylation of the retinoblastoma (Rb) protein was decreased in SBC-5 cells. In addition, TPY-835 induced an increase of the sub-G1 phase cell population after 48-72 h treatment. The growth inhibitory effects of TPY-835 against cisplatin (CDDP)-, camptothecin- and 5-FU-resistant cell lines are comparable to the growth inhibitory effect on their parental lines, thus indicating that TPY-835 did not show cross-resistance to these cell lines. These results suggest that TPY-835 is a promising candidate for constructing a novel class of antitumor agents that can control the cell cycle progression of cancer cells.
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PMID:A novel cinnamic acid derivative that inhibits Cdc25 dual-specificity phosphatase activity. 1612 47

Research on developing molecular diagnostics for hereditary cancers resulted in establishing diagnostic services for familiar polyposis and non-polyposis patients (mutation determination of APC, MYH, STK11, SMAD4, MLH1, MSH2). In familiar testicular cancers the role of gr/gr gene on Y chromosome was identified. Molecular diagnostic tool was established to monitor the progression of follicular lymphoma using Bcl-2/IgH fusion sequences. Molecular diagnostic tools were developed to monitor circulating endothelial precursor cells (CEP) as well and the technique was tested in lung cancer patients. In malignant melanoma we have tested several potential novel markers among which ryanodine receptor seems to be a promising one, while the functional P2X7 receptor may serve as a therapeutic target. We have determined the tyrosine kinase "kinome" profile of HER-2-amplified breast cancers. Furthermore, the "kinome" profile was found to be characteristic for head and neck cancers of various anatomical location. Based on previous studies on the anti-migratory and antimetastatic potential of low-molecular-weight heparins, we have identified short heparin-derived oligosaccharides with maintained antimetastatic- but non-anticoagulant potentials. Pharmacogenomic studies on the role of polymorphism of the serine-hydroxymethyl-transferase (SHMT) gene in the efficacy of 5-FU and FOLFIRI protocols of colorectal cancer patients revealed a significant effect resulting in altered overall survival as well.
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PMID:[Developments in cancer management by innovative genomics. 2006 report of the National Cancer Consortium]. 1721 11

In order to construct plasmid of hypoxia-inducible factor-1alpha (HIF-1alpha), and transfect into human lung cancer cells A549, the change in sensitivity of lung cancer cells A549 to chemotherapy was observed. HIF-1alpha mRNA structure region was amplified by RT-PCR and inserted into plasmid pcDNA3. The expression plasmid pcDNA3/HIF-1alpha was transfected into A549 with Lipofec-tAMINE2000. The expression of HIF-1alpha protein was detected by Western blot. After A549 cells were transfected with HIF-1alpha prior to addition of 5-Fu, the growth activity was measured by growth curve, apoptosis was detected by flow cytometry at 48 h, and the levels of caspase3 and MDR-1 were determined by Western blot. The results showed that the constructed expression plasmid was analyzed with restriction enzymes and gel electrophoresis. Two DNA lanes at 2.55 kb and 5.4 kb respectively were found, which were consistent with that expected. The growth rate in 5-Fu group was significantly inhibited, and the apoptosis index and caspase3 activity were increased significantly as compared with control group. After HIF-1alpha being transfected into A549, the activity of MDR-1 was increased and the effect of 5-Fu was weakened. In conclusion, HIF-1alpha can promote chemoresistance by increasing the activation of MDRI and suppressing apoptosis during lung cancer cells A549 induced with 5-Fu.
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PMID:Hypoxia-inducible factor-1alpha suppressing apoptosis and increasing tolerance of lung cancer cells to chemotherapy. 1721 56

Differently from target-based anticancer drugs, molecular mechanisms of actions are not well-known in many of the classical antineoplastic agents. With the exception of vinca alkaloids and taxanes, all of the classical antineoplastic agents work on DNA metabolism in cells and can therefore be categorised as 'DNA metabolism inhibitor'. Cellular sensitivity against these drugs largely depends on various activities in DNA metabolism, particularly in DNA repair. However, DNA repair as a determinant of drug sensitivity had long received little attention. DNA mismatch repair (MMR) is now regarded as an important determinant to alter cellular sensitivities against various drugs including fluoropyrimidines, platinum compounds and topoisomerase inhibitors. However, molecular mechanisms of this connection are still unknown. In particular, the relationship between MMR and 5-fluorouraci (l 5-FU) sensitivity is now being approached by examining the tumour MMR status and clinical outcomes in colorectal cancer patients treated with 5-FU-based adjuvant chemotherapies. However, reported results lack consistency, possibly due to the methodological problems in assays used to determine the MMR status. On the other hand, nucleotide excision repair (NER) is also regarded as an important determinant of cisplatin (CDDP) sensitivity. Expression of ERCC 1, a component of this complex multi-protein system, has been reported to be a determinant of prognosis in CDDP-treated non-small-cell lung cancer patients. In order to establish the significance of DNA repair as a determinant of tumour chemosensitivity, further basic studies, particularly ones approached from biochemical viewpoints, are required. Clinical studies supported by accurate assay techniques are also needed.
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PMID:[DNA repair as a determinant of tumour chemosensitivity]. 1735 24

Etoposide, a podophylotoxin anticancer agent, induces apoptotic cell death in normal and cancer cells. Etoposide-induced apoptosis plays a role in not only anticancer effect but also adverse reaction, such as myelosuppression. Since we have found that wogonin, a flavone found in Scutellaria baicalensis Georgi, prevents thymocyte apoptosis induced by various compounds including etoposide, we examined the effect of this flavone on etoposide-induced apoptosis in cancer cells. Although 100 muM wogonin itself significantly increased DNA fragmentation in HL-60 cells, this change was not observed in Jurkat cells. On the other hand, this flavone significantly potentiated etoposide-induced apoptosis in Jurkat and HL-60 cells. Similarly, wogonin accelerated etoposide-induced cell death in lung cancer cells. Since wogonin had no effect on the action of other anticancer agents, such as 5-FU and cisplatin, this flavone seems to accelerate only etoposide-induced apoptotic cell death in cancer cells. These results suggest that the modification of etoposide-induced apoptosis by wogonin may be available to reduce the adverse reaction of this agent.
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PMID:Wogonin, a plant flavone, potentiates etoposide-induced apoptosis in cancer cells. 1740 65

The prognosis of a colorectal cancer patient with unresectable hepatic metastases is extremely poor. To improve the prognosis, when the hepatic metastases were initially unresectable, we performed second-look hepatectomy (s-l hepatectomy) after neoadjuvant hepatic arterial 5-FU infusion plus UFT (HAI-PMC). Here, we report the case of a sigmoid colon cancer patient with initially unresectable hepatic metastases showing a prolonged survival (6.5 years) by second-look operation after HAI-PMC. A 57-year-old woman was diagnosed with sigmoid colon cancer with unresectable liver metastases. Sigmoidectomy and hepatic arterial catheterization were performed in the initial operation, and HAI-PMC was performed 6 months after. Metastatic foci of the liver had shrunk (90.9%), but solitary metastatic lung cancer was detected during HAI. As no other metastatic lesion was observed, partial resection of the liver and lung was performed as a second-look operation, 6 months after the initial operation. The woman continued venous infusion chemotherapy as an outpatient, and she survived for 6.5 years after the initial operation. This result suggests that strategic multidisciplinary treatment utilizing s-l hepatectomy after neoadjuvant chemotherapy can lead to better prognosis for colorectal cancer patients with hepatic metastases.
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PMID:[A long survival case of sigmoid colon cancer patient with initially unresectable hepatic metastases]. 1743 55

S-1 is an oral fluorouracil anticancer drug that contains the 5-FU prodrug tegafur. Tegafur has been shown to be converted enzymatically to 5-FU to exert its antitumor effect, and this conversion is principally catalyzed by CYP2A6. Forty-six non-small-cell lung cancer patients were enrolled. The frequencies of the CYP2A6*4C, CYP2A6*7, and CYP2A6*9 alleles were 17.4, 19.6, and 15.2%, respectively. In the S-1 pharmacokinetic analysis, the area under the concentration-time curve from 0 to 10 h (AUC(0-10)) ratios of 5-FU/tegafur showed large interindividual variabilities, ranging from 5.14 to 112.6. The AUC(0-10) for tegafur was 1.5-fold higher in patients with the CYP2A6*4C allele than in patients without the CYP2A6*4C allele P < 0.05). Furthermore, patients with the CYP2A6*4C allele had a significantly lower maximum plasma concentration (102.6 +/- 32.9 ng/ml) for 5-FU than patients without the CYP2A6*4C allele (157.0 +/- 65.5 ng/ml, P < 0.05). Genotyping of CYP2A6 polymorphisms may provide vital information for effective cancer therapy using S-1.
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PMID:The CYP2A6*4 allele is determinant of S-1 pharmacokinetics in Japanese patients with non-small-cell lung cancer. 1838 65

Using a selection process designed to reflect clinically relevant conditions, a panel of taxane-selected variants were developed to study further the mechanisms of resistance in lung cancer. Unlike continuous or pulse exposure to high concentrations of chemotherapeutic drugs which yield high resistance and often cross resistance, most variants developed here displayed low level resistance to the selecting drug with slight cross-resistance. Pulsing with taxol resulted in more highly resistant clones (up to 51.4-fold). Analysis of taxol and taxotere in the four major lung cancer cell types showed the taxanes to be more effective against NSCLC (with the exception of SKMES-taxane selected variants) than against the SCLC. Comparison of taxol and taxotere shows that taxol induces higher levels of resistance than taxotere. Further, in taxotere-selected cell lines, the cells are more resistant to taxol than taxotere, suggesting that taxotere may be a superior taxane from a clinical view. Taxol treatment resulted in increased cross-resistance to 5-FU in all classes of lung cancer except DMS-53. The high levels of Pgp in the DMS-53 and selected variant suggests this mechanism is not related to Pgp expression. Analysis of the Pgp and MRP-1 status by combination inhibitory assays and Western blotting showed no consistent relationship between expression of the membrane pumps Pgp or MRP-1 and resistance. However, where high level resistance was seen, the parent cell line expressed Pgp or MRP-1 and was accompanied by increased levels in the variants. Overall we found that the clinically relevant models used here are useful for investigating mechanisms of taxane resistance.
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PMID:Development of taxane resistance in a panel of human lung cancer cell lines. 1851 76


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