Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0149925 (small cell lung cancer)
 6,491 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Small cell lung cancer (SCLC) occurs as two neuroendocrine subtypes, SCLC-C (classic) and SCLC-V (variant). One reported difference is elevated levels of diphosphodiesters (DPDE) in the more differentiated SCLC-C subtype. DPDE have been identified as primarily UDP-N-acetylhexosamines (UDP-NAH) in a variety of tumors, and changes in DPDE levels have been observed during experiments designed to induce cell differentiation. UDP-NAH synthesis is controlled by negative feedback regulation of glutamine:fructose-6-P amidotransferase (EC 2.6.1.16), which can be circumvented by glucosamine. Using 31P nuclear magnetic resonance analysis of extracts and perfused cells, we have identified UDP-N-acetylglucosamine and UDP-N-acetylgalactosamine as the primary metabolites in the DPDE spectral region of SCLC-V N-417 cells. Glucosamine addition causes a rapid increase in UDP-NAH levels. At glucosamine: glucose ratios of 1:1 and 10:1 formation of the UDP-NAH intermediates N-acetylglucosamine 6-phosphate and UDP-N-acetylglucosamine 1-phosphate is also observed, indicating UTP limitation. Subsequent uridine addition results in depletion of the intermediates and increased UDP-NAH formation. Moreover, N-417 cells retain the capacity to rapidly convert uridine to UTP despite low ATP and phosphocreatine levels. This expansion of the uridine pool may represent an additional metabolic reserve not yet addressed in the design of therapy options.
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PMID:UDP-N-acetylhexosamine modulation by glucosamine and uridine in NCI N-417 variant small cell lung cancer cells: 31P nuclear magnetic resonance results. 131 32

Early effects of irradiation were evaluated by non-invasive in vivo 31P-magnetic resonance spectroscopy (31P-MRS) of two small cell lung cancer (SCLC) tumor lines CPH SCCL 54A and 54B, in nude mice. The tumors were originally derived from the same patient and have similar morphology and growth characteristics, but a different radiosensitivity. The 54A tumors are twice as radiosensitive as the 54B's. In the present study the tumors were treated with 2.5, 10, and 40 Gy. For comparison, nude mice were given cranial irradiation at the same three doses, and the effect was evaluated by in vivo 31P-MRS. No effect was observed in brain at any dose level. In contrast, 40 Gy induced a statistically significant reduction in ATP/Pi ratio during the 12-h post-irradiation period. This effect was more pronounced in 54A than in 54B. Some reduction was observed following 10 Gy, whereas 2.5 Gy induced no changes in ATP/Pi. The differential effect on tumors and brain might be relevant for monitoring irradiation effects by in vivo 31P-MRS in patients with brain metastases.
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PMID:Different early effect of irradiation in brain and small cell lung cancer examined by in vivo 31P-magnetic resonance spectroscopy. 132 55

Two human small cell lung cancer tumor lines, maintained as solid tumor xenografts on nude mice and as in vitro cell cultures, were studied by in vivo 31P magnetic resonance spectroscopy and by biochemical analysis of extracts of solid tumors and cell cultures. The tumor lines CPH SCCL 54A and CPH SCCL 54B are subpopulations from the same tumor. In solid tumors (n = 125), the ATP/Pi ratio was greater in 54A than in 54B. This was due to a higher ATP level in 54A, whereas there was no difference in Pi, ADP, and AMP. A decrease in ATP/Pi during growth was caused by a decline in ATP, whereas Pi remained unchanged. Small amounts of phosphocreatine were found in the xenografts and in tumor extracts, but not in the cell extracts; correspondingly, there was a low creatine kinase activity in solid tumors and no activity in the cell cultures. Thus, the phosphocreatine content of the solid tumors originated from the stroma. A difference in ATP content between 54A and 54B was also found in cell cultures; hence, the metabolic difference is an intrinsic quality of the malignant cells and is not caused by the host system.
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PMID:Different energy metabolism in two human small cell lung cancer subpopulations examined by 31P magnetic resonance spectroscopy and biochemical analysis in vivo and in vitro. 165 47

31P magnetic resonance spectroscopy (31P MRS) and biochemical analysis of extracts were applied to study the metabolic response to X-irradiation of small cell lung cancer in nude mice. Two small cell lung cancer xenografts, CPH SCCL 54A and 54B, with different radiosensitivity, although derived from the same patient, were studied. A total of 126 individual tumors were examined. Following 5.0-Gy irradiation, a reversible increase in the ATP/Pi ratio, reaching twice the pretreatment level within 2 wk, was observed with 31P MRS, while 20 Gy induced a reversible decrease in the ATP/Pi ratio. The t1/2 of this decline was 2 to 3 h for 54A and about 6 h for the less radiosensitive 54B. The 31P MRS data were compared with biochemical analysis of tumors freeze-clamped and extracted at similar intervals after 20 Gy. It appeared that an acute reversible increase in Pi concentration was the major cause of the ATP/Pi decrease induced by 20 Gy. A linear correlation between ATP/Pi estimated by 31P MRS and by analytical biochemistry was found. The ATP/Pi ratio may be valuable for early assessment of radiosensitivity of small cell lung cancer tumors.
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PMID:Early effects of radiotherapy in small cell lung cancer xenografts monitored by 31P magnetic resonance spectroscopy and biochemical analysis. 216 49

Overexpression of multidrug resistance-associated protein (MRP) has been detected in resistant cell lines derived from a variety of tumor types. The deduced amino acid sequence of MRP suggests that it is a member of the ATP-binding cassette transmembrane transporter superfamily that may be glycosylated and/or phosphorylated [S. P. C. Cole et al., Science Washington, DC), 258: 1650-1654, 1992]. Recently, transfection of HeLa cells with MRP expression vectors has demonstrated that the protein is capable of increasing resistance to natural product drugs such as anthracyclines, Vinca alkaloids, and epipodophyllotoxins (C. E. Grant et al., Cancer Res., 54: 357-361, 1994). Although the resistance phenotype of the transfectants is similar to that of the human small cell lung cancer cell line, H69AR, from which MRP was originally cloned, the transfectants differ in their drug accumulation characteristics, relative resistance to certain drugs, and MRP mRNA:protein ratio. Such differences have also been observed among drug-selected cell lines that overexpress MRP, and the underlying causes of these variable phenotypes are presently not known. We have utilized polyclonal anti-MRP-peptide antibodies to compare MRP post-translational modification, stability, processing, and subcellular distribution in the HeLa transfectants and in the drug-selected H69AR cells. These studies establish that MRP in both the transfected and selected cells is an ATP-binding, integral membrane glycophosphoprotein with an apparent molecular weight of 190,000. No obvious differences were detected in the extent or type of glycosylation or the kinetics of processing and turnover of the protein that might contribute to the different characteristics of the transfected and drug-selected cells. Analyses of the subcellular distribution of MRP by isopyknic density gradient centrifugation revealed that approximately 80% of MRP in the HeLa transfectants was associated with a low density plasma membrane fraction while the comparable fraction in the drug-selected H69AR cells contained only approximately 50% of the protein. The remaining MRP and plasma membrane markers were codistributed in higher density fractions consistent with the presence of MRP in endocytotic vesicles. The relatively high proportion of MRP associated with these fractions in H69AR cells may contribute to the lack of an observable accumulation defect in these cells when compared with the transfectants.
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PMID:Characterization of the M(r) 190,000 multidrug resistance protein (MRP) in drug-selected and transfected human tumor cell. 780 19

In several multidrug resistant tumor cell lines without overexpression of P-glycoprotein (non-Pgp MDR), a decreased accumulation of drugs has been shown to contribute to resistance. We have recently reported that daunorubicin (DNR) accumulation was decreased in the multidrug resistance-associated protein overexpressing GLC4/ADR non-Pgp MDR small cell lung cancer cell line due to an enhanced energy-dependent efflux which could be inhibited by the isoflavonoid genistein. The purpose of this work was 2-fold: (i) to investigate the mechanism by which genistein inhibits the DNR efflux in the GLC4/ADR cells; and (ii) to characterize the dependence of DNR transport on ATP concentration in intact GLC4/ADR cells. The active transport of DNR in GLC4/ADR cells appeared to be a saturable process with an apparent Km of DNR of 1.4 +/- 0.4 microM. Genistein increased the apparent Km value of DNR, suggesting that this agent is a competitive inhibitor of DNR transport. These data provide additional evidence that energy-dependent DNR transport in GLC4/ADR cells is a protein-mediated process. In addition, genistein decreased cellular ATP concentration in a dose-dependent manner in sensitive as well as in resistant cells. Marked inhibition of DNR transport activity in intact GLC4/ADR cells was found when cellular ATP concentration was decreased below 2 mM by sodium azide or 2-deoxy-D-glucose. Thus, since DNR transport in intact GLC4/ADR is already inhibited at modest cellular ATP depletion, a limitation in ATP supply might open ways to make MDR cells more susceptible to drug toxicity.
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PMID:Competitive inhibition by genistein and ATP dependence of daunorubicin transport in intact MRP overexpressing human small cell lung cancer cells. 794 6

Lonidamine is an antispermatogenic and anticancer drug that is believed to act by inhibition of energy metabolism. In this study, the effects of Lonidamine on the concentration of intracellular free Ca2+ of several tumor cell lines were assessed because of the important role that cytosolic Ca2+ plays in cell viability and proliferation. The presence of 300 microM Lonidamine resulted in large elevations of cytosolic Ca2+ (> 100 nM) in AS-30D rat ascites hepatoma cells and in cultured EMT6 murine mammary adenocarcinoma cells but had little effect on cultured NCI-H345 human small cell lung cancer cells. The apparent EC50 for Lonidamine was approximately 175 microM. The source of elevated cytosolic Ca2+ was primarily intracellular stores, and the effects of Lonidamine on Ca2+ efflux from these stores did not appear to be due to an ionophoretic action of this compound or to a decline in the level of cellular ATP. These results indicate that the Ca2+ homeostasis of certain lines of tumor cells is specifically altered by Lonidamine at concentrations known to affect cell proliferation.
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PMID:Non-ionophoretic elevation of intracellular Ca2+ by Lonidamine. 834 57

Tumours express a variety of novel epitopes which represent potential immune targets, and thus clinically evident tumours are thought to have effectively avoided immune recognition and elimination. Transporters associated with antigen presentation (TAP) are thought to be responsible for conveying intracellular peptides into the endoplasmic reticulum for complex formation with class I MHC and subsequent recognition by cytotoxic T lymphocytes. In this study, we evaluated 79 human solid tumours and cell lines for genetic abnormalities in TAP1 that might have led to an acquired loss of antigen presenting ability. A novel sequence (R659Q) was discovered near the ATP binding site in a human small cell lung cancer (SCLC) cell line, H1436. This cell line is heterozygous for this allele, but only the R659Q allele is transcribed into RNA. Even though the R659Q protein is expressed, these cells act as if they were TAP deficient by peptide binding and antigen presentation studies, which are restored after transfection of a functional TAP1 allele. This is the first evidence for a naturally occuring protein structural defect resulting in defective peptide transport in a human solid tumour.
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PMID:A functionally defective allele of TAP1 results in loss of MHC class I antigen presentation in a human lung cancer. 864 Feb 13

The complex catalytic cycle of topoisomerase II is the target of important antitumor agents. Topoisomerase II poisons, such as etoposide and daunorubicin, inhibit the resealing of DNA breaks created by the enzyme. This enzyme-coupled cell kill is susceptible to pharmacological regulation by drugs interfering with other steps in the enzyme's catalytic cycle (i.e. so-called catalytic inhibitors). From in vitro studies, is appears that there are 2 distinct sites in the cycle at which a complete antagonism of the toxicity of topoisomerase II poisons can be obtained. The first is the inhibition of the enzyme's binding to its DNA substrate as seen with intercalating drugs such as chloroquine and aclarubicin; a second, more specific, interaction is elicited by bisdioxopiperazines, which are thought to lock the homodimeric topoisomerase II in the form of a closed bracelet surrounding the DNA at the postreligation step. To investigate these in vitro findings in the more complex whole cell system, we studied enzyme-DNA binding in Western blots of 0.35 M NaCL nuclear extracts from human small cell lung cancer OC-NYH cells incubated with the bisdioxopiperazine ICRF-187 and aclarubicin. With ICRF-187, we found a reversible ATP dependent decrease in the extractable levels of both the alpha and the beta isoforms of topoisomerase II. In contrast to ICRF-187, aclarubicin increased the amount of extractable enzyme from cells. Further, when using the terpenoid clerocidin, which differs from conventional topoisomerase II poisons by forming a salt-and heat-stable inhibition of DNA resealing, no antagonism was found by ICRF-187 on formation of DNA strand breaks and cytotoxicity. However, aclarubicin, which interferes early in the topoisomerase II catalytic cycle, was able to antagonize DNA breaks and cytotoxicity caused by clerocidin. The results indicate 4 different steps in the topoisomerase II cycle that can be uncoupled in the cell by different drug types: etoposide and clerocidin cause reversible and irreversible inhibition of DNA resealing, respectively, and DNA intercalating agents, such as aclarubicin, inhibit binding of topoisomerase II enzyme to its DNA substrate. Finally, bisdioxopiperazines as ICRF-187 partake in an energy dependent inappropriate binding of topoisomerase II to DNA after the resealing step. This knowledge may enable the design of rational combinations of topoisomerase II poisons and catalytic inhibitors to enhance the efficacy of anticancer therapy.
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PMID:Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and catalytic inhibitors (aclarubicin, ICRF-187) to four distinct steps in the topoisomerase II catalytic cycle. 865 36

Cell lines, LC-5 and LC-172, were established from tumors of a small cell lung cancer patient prior to and after combination chemotherapy including etoposide (VP-16), when drug-resistant tumors developed in relapse. A VP-16-resistant cell line, LC-172/VP, was selected from the LC-172 cells in culture in multiple steps with VP-16. LC-172 cells were 3.5-fold resistant to VP-16 in growth inhibition, and 3.3-fold resistant to adriamycin as compared with LC-5 cells. LC-172/VP cells showed large differences in cross-resistance to topoisomerase II-targeting drugs such as VP-16, 200-fold, adriamycin, 10-fold, and MST-16, 4.3-fold; the cells were moderately refractory, 5.5-fold, to vincristine. VP-16 accumulation in the cells was similar in three cell lines. Topoisomerase II unknotting activity was reduced 7- to 10-fold in LC-172/VP and 1.5- to 2-fold in LC-172 cells compared with LC-5 cells, while relaxing activity of topoisomerase I appeared to be unchanged. Topoisomerase II protein was also reduced 5- to 10-fold in LC-172/VP and marginally so in LC-172 cells. Topoisomerase II alpha and II beta were each reduced 10-fold and 2-fold, respectively, in LC-172/VP cells, while they were both slightly decreased (-1.5-fold), respectively, in LC-172 cells compared with LC-5 cells. No apparent alteration in ATP requirement for catalytic activity and in sensitivity to VP-16 was observed for topoisomerase II from the three cell lines. Taken together, these results suggested that resistance to VP-16 in LC-172 and LC-172/VP is associated with a quantitative reduction in expression of topoisomerase II alpha of the parental type.
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PMID:Reduced expression of DNA topoisomerase II confers resistance to etoposide (VP-16) in small cell lung cancer cell lines established from a refractory tumor of a patient and by in vitro selection. 889 98


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