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)

A cisplatin(CDDP)-resistant subline of a human lung cancer cell line, PC-7/CDDP, was 4.7-fold more resistant to CDDP than the parent line in a colony-forming assay. The sensitivity of this cell line to anthracyclines, vinca-alkaloid, etoposide, mitomycin C, and bleomycin was similar to that of the parental line, PC-7. However, PC-7/CDDP exhibited 4-fold higher sensitivity to fluorouracil (FUra). Possible mechanisms associated with the collateral sensitivity to FUra were studied in PC-7/CDDP cells. The sensitivity of both cell lines to FUra did not correlate with the effect of FUra on RNA. On the other hand, FUra induced a greater reduction in dTTP pools and more single strand breaks in PC-7/CDDP than in PC-7 cells. These results suggest that the pathway for de novo deoxyribonucleotide synthesis may be a target for FUra in PC-7/CDDP cells. However, inhibition of thymidylate synthase after FUra treatment did not correlate with the DNA-directed activity of FUra. Based on the above findings, the decreased salvage synthesis of dTTP was considered a possible mechanism of the greater reduction of dTTP pools in PC-7/CDDP cells. However, the activity of dThd kinase was the same in both cell lines. In the presence of physiological concentrations of exogenous dThd in the serum, uptake of dThd was less in PC-7/CDDP cells than that in PC-7 cells. Our data suggest that FUra-induced cytotoxicity in PC-7/CDDP cells is associated with the inhibition of dTTP synthesis and that the decreased uptake of dThd is a possible mechanism of the collateral sensitivity to FUra in PC-7/CDDP cells.
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PMID:Mechanisms of collateral sensitivity to fluorouracil of a cis-diamminedichloroplatinum(II)-resistant human non-small lung cancer cell line. 131 27

A 6.2-fold cis-diamminedichloroplatinum(II) (CDDP) resistant human lung cancer cell line (A549/CDDP5), which was capable of proliferating in the presence of 5 microM CDDP, was developed. Compared to the parent cell line, A549/CDDP5 subline had a significantly longer doubling time, increased population of S phase, enhanced sensitivity to 5-FU and elevated activities of dTMP synthase (EC 2.1.1.45) and thymidine kinase (EC 2.7.1.21) by 5.4- and 2.0-fold of the parent cells. These results suggest that the capacity of dTMP synthesis might have an important role in the acquisition of CDDP resistance of A549 cells.
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PMID:Establishment and biochemical properties of cis-diamminedichloroplatinum(II)-resistant A549 lung cancer cells. 184 10

Reduced folates have been shown to increase the cytotoxicity of 5-fluorouracil (FUra) by stabilizing the fluorodeoxyuridine monophosphate:thymidylate synthase complex, thus increasing the block in the DNA synthetic pathway. Using an in vitro tetrazolium colorimetric (MTT) cytotoxic assay, we tested the effects of FUra and 5-fluorodeoxyuridine (FUdR) with and without leucovorin (LV) on a panel of 7 human lung cancer cell lines. LV at a concentration of 20 microM enhanced the cytotoxicity of FUra and of FUdR in all of the cell lines. Quantitatively, LV had a higher degree of enhancement on FUdR than on FUra cytotoxicity in 6 cell lines. There was equivalent enhancement in the only remaining line. The differential effects of LV on the cytotoxicity of FUra vs. FUdR in these lung carcinoma lines contrasts with a quantitatively similar enhancement of cytotoxicity between FUra and FUdR in colon cancer lines previously reported from our laboratory. This suggests that the metabolism of FUra may be different in these lung cancer cell lines.
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PMID:Enhancement of fluorinated pyrimidine-induced cytotoxicity by leucovorin in human lung cancer cell lines. 216 87

We have characterized the determinants of methotrexate (MTX) responsiveness in eight patient-derived cell lines of small-cell lung cancer (SCLC). Clonogenic survival was correlated with factors known to affect sensitivity to drug. NCI-H209 and NCI-H128 were most drug sensitive, with drug concentrations required to inhibit clonogenic survival by 50% with less than 0.1 microM MTX. Six cell lines (NCI-H187, NCI-H345, NCI-H60, NCI-H524, NCI-H146, and NCI-N417D) were relatively drug resistant. In all cell lines studied, higher molecular weight MTX-polyglutamates (MTX-PGs) with 3-5 glutamyl moieties (MTX-Glu3 through MTX-Glu5) were selectively retained. Relative resistance to low (1.0 microM) drug concentrations appeared to be largely due to decreased intracellular metabolism of MTX. Five of the six resistant lines were able to synthesize polyglutamates at higher (10 microM) drug concentrations, although one resistant cell line (NCI-N417D) did not synthesize higher molecular weight MTX-PGs, even after exposure to 10 microM drug. Two cell lines with resistance to 10 microM MTX (NCI-H146 and NCI-H524) synthesized and retained higher molecular weight MTX-PGs in excess of binding capacity after exposure to 10 microM drug. However, the specific activity of thymidylate synthase in these cell lines was low. MTX sensitivity in patient-derived cell lines of SCLC requires the ability of cells to accumulate and retain intracellular drug in the form of polyglutamate metabolites in excess of dihydrofolate reductase, as well as a high basal level of consumption of reduced folates in the synthesis of thymidylate.
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PMID:Determinants of the sensitivity of human small-cell lung cancer cell lines to methotrexate. 241 16

Thymidylate synthase was identified at the cellular level using anti-thymidylate synthase monoclonal antibody (M-TS-4) developed against HeLa cell line. HeLa cells, 9L rat gliosarcoma cells, and some of human brain tumor cells (medulloblastoma, metastatic brain tumors from lung cancer and osteosarcoma) were cultured in complete medium for 72 hr and fixed with 10% buffered formalin. These were covered with 1:20 dilution of M-TS-4 in Burridge buffer and 1% bovine serum albumin for 4 or 24 hr. After rinsing twice with phosphate-buffered saline solution (PBS), the cell staining was made with avidin-biotin peroxidase complex (ABC). In addition, HeLa cells were exposed to 2 microCi/ml of tritiated thymidine for 30 min, cultured again for 0 to 5 hr, and subjected to autoradiography after M-TS-4 staining with ABC. All cells were stained satisfactorily with ABC except 9L rat gliosarcoma cells. Autoradiography revealed that 38% of the cells were stained with ABC, 28% were labeled with tritiated thymidine, while only 8% of the cells were stained simultaneously at 0 hr specimen. However, the cells labeled with both agents subsided when the cells were incubated in complete medium for 1 or 2 hr before fixation. Therefore, thymidylate synthase appears to exist mainly in G1-phase and to subside in early S-phase. Although the number of thymidylate synthase positive cells was greater than that of the cells labeled with tritiated thymidine, the ratio was constant (r = 0.99). The fraction of S-phase can be estimated from that of thymidylate synthase positive cells. Thymidylate synthase positive cell fraction may become another important segment for cell cycle analysis.
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PMID:[Cell kinetic studies using monoclonal antibody to thymidylate synthase]. 244 34

Compared to either compound alone, the combination of acivicin and cis-diamminedichloroplatinum(II) markedly enhanced the inhibition of the activities of thymidylate synthase and thymidine kinase, the enzymes involved in the final steps of the de novo and salvage pathways in pyrimidine metabolism in A549 lung cancer cells. The enhancement of enzymic inhibition paralleled that of cell growth inhibition. These results indicate that the combination of these drugs can inhibit the capacities of the pyrimidine pathways, resulting in an efficient reduction of DNA synthesis.
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PMID:Effects of the combination of acivicin and cis-diamminedichloroplatinum(II) on thymidylate synthesis of A549 lung cancer cells. 273 Jun 61

Dipyridamole potentiates the cytotoxicity of N10-propargyl-5,8-dideazafolic acid (CB3717), an antifolate inhibitor of thymidylate synthase, by inhibiting both thymidine (TdR) salvage and deoxyuridine (UdR) efflux. Dipyridamole binds to the serum component alpha 1acid glycoprotein (alpha 1AGP) and hence the effects of alpha 1AGP on dipyridamole-induced changes in nucleoside transport and CB3717 cytotoxicity have been investigated. Using A549 lung cancer cells in vitro, alpha 1AGP reduced the inhibition of nucleoside transport by dipyridamole in a concentration-dependent manner. Between 10 and 200 times the concentration of dipyridamole was needed to inhibit TdR uptake to the same degree in medium containing 1 mg/ml alpha 1AGP (a physiological concentration) when compared to the uptake in alpha 1AGP-free medium. Although dipyridamole inhibited UdR efflux more than TdR efflux, inhibition of UdR efflux was reduced less than the inhibition of TdR efflux in the presence of 1 mg/ml alpha 1AGP. Thus, clinically achievable levels of dipyridamole (2.5-7.5 microM), even in the presence of physiological alpha 1AGP concentrations, caused significant inhibition of nucleotide uptake and efflux. The cytotoxicity of CB3717 was increased 2-3-fold by 3 and 10 microM dipyridamole in alpha 1AGP-free medium, whereas dipyridamole did not significantly (P greater than or equal to 0.05) potentiate CB3717 cytotoxicity in the presence of 1 mg/ml alpha 1AGP. Measured free dipyridamole levels indicated that the impaired inhibition of nucleoside transport and the lack of potentiation of CB3717 cytotoxicity in the presence of alpha 1AGP was due solely to the binding of dipyridamole to alpha 1AGP. It is concluded that alpha 1AGP levels will be a major determinant of the ability of dipyridamole to modulate the activity of antimetabolites in vivo.
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PMID:Modulation of dipyridamole action by alpha 1 acid glycoprotein. Reduced potentiation of quinazoline antifolate (CB3717) cytotoxicity by dipyridamole. 281 27

The expression of several resistance markers (P-glycoprotein, glutathione S-transferase-pi, thymidylate synthase, dihydrofolate reductase) was analyzed in matched primary tumors and lymph node metastases from 21 patients with lung cancer using immunohistochemistry. The analysis showed that expression of these resistance proteins is generally congruent in primary lung cancer and simultaneously resected lymph node metastases. This suggests that in general the resistance of a primary tumor predicts for the resistance of the metastases and vice versa.
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PMID:Detection of resistance proteins in matched primary lung tumors and lymph node metastases. 791 93

Fluorodeoxyuridine (FUdR), the deoxynucleoside metabolite of 5-fluorouracil (5-FU), can be converted in a single step to fluorodeoxyuridine monophosphate (FdUMP), which binds covalently to thymidylate synthase (TS). Ribonucleotide reductase, an obligatory enzyme in the synthesis of deoxynucleotides, can be inhibited by hydroxyurea. Recognizing the well-established synergism between 5-FU and folinic acid (leucovorin), we hypothesized that the simultaneous administration of FUdR, leucovorin, and hydroxyurea might afford more effective inhibition of TS. Thirty-six patients with neoplastic disease considered refractory to standard therapy were entered into this phase I protocol. Treatment was administered on days 1 through 5 of a 28-day cycle and consisted of folinic acid (500 mg m-2 day-1) and FUdR at escalating doses of 0.1, 0.15, or 0.2 mg kg-1 day-1 both administered by continuous i.v. infusion, and hydroxyurea given p.o. once per day at doses ranging from 0 to 250o mg in 500-mg increments. The hydroxyurea and FUdR levels were escalated in a sequential fashion. The majority of patients had refractory breast or lung cancer. Dose-limiting toxicities were mucositis and diarrhea at the maximally tolerated dose of 0.15 mg/kg FUdR and 2000 mg hydroxyurea per day in conjunction with high-dose folinic acid. Hematological toxicity was minor. Of the 18 patients in whom response could be evaluated, none had evidence of objective disease regression. Mucositis and diarrhea are the dose-limiting toxicities when continuous infusions of FUdR and high-dose folinic acid are combined with oral hydroxyurea, effects that are consistent with the observed toxicities for FUdR when administered alone or in combination with leucovorin.
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PMID:Phase I study of 5-day continuous infusion fluorodeoxyuridine and high-dose folinic acid with oral hydroxyurea. 798 94

Anticancer drug development has recently shifted in part to development of more innovative anticancer agents. The increasing knowledge of the pathogenetic mechanisms involved in cancer cell growth has enabled the introduction of drug screening that is more mechanism-based. The realization that new targets should be preferentially evaluated as sites for anticancer drug treatment has led to the introduction of drugs such as the taxanes. Following this logic, several new drugs are being developed. Minor groove-binding agents such as carzelesin and oral platins lacking organ toxicity, such as JM216, have recently entered clinical studies. The activity of gemcitabine is a result of its being a cytidine analogue and being competitively incorporated by DNA; the drug has shown interesting activity in non-small-cell lung cancer and, although registration is imminent, issues regarding the optimal dose and administration schedule have yet to be resolved. Tomudex is a thymidylate synthase inhibitor with interesting activity in colorectal cancer. Activity in colorectal cancer is also of interest for irinotecan, the first clinically applied topoisomerase I inhibitor, an enzyme that is another example of a new target for anticancer drugs. Irinotecan has produced consistent response rates of 20-30% in six different studies in colorectal cancer. The other topoisomerase I inhibitor that is in the advanced stage of development is topotecan. This drug has shown activity in second-line chemotherapy for ovarian cancer and small-cell lung cancer. Another interesting feature of topotecan is the availability of an oral formulation with consistent bioavailability. Drugs interfering with cellular signal transduction, such as the protein kinase C inhibitors, are in the development spotlight. Finally, the use of old drugs in new ways, such as immunoconjugates of doxorubicin, holds promise for the near future.
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PMID:New promising anticancer agents in development: what comes next? 876 8


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