Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mechanisms contributing to reduced cytotoxic drug accumulation were studied in two multidrug-resistant (MDR) human lung cancer cell lines without P-glycoprotein expression. In these (non-small cell) SW-1573/2R120 and (small cell) GLC4/ADR MDR cells, the steady-state accumulation of [14C]daunorubicin was 30 and 12%, respectively, of that in the parent cells. When cells, at steady state, were permeabilized with digitonin, the amount of daunorubicin binding increased only in the resistant cells. The reduced accumulation of daunorubicin in the SW-1573/2R120 and GLC4/ADR cells was accompanied by a lower initial (2 min) uptake rate of this drug. No difference in initial efflux rate of daunorubicin from preloaded cells could be detected between sensitive and resistant SW-1573 cells. However, daunorubicin was extruded 5-fold faster from GLC4/ADR cells than from the parental cells. In the presence of the energy metabolism inhibitors sodium azide and deoxyglucose, the reduced daunorubicin accumulations in the SW-1573/2R120 and GLC4/ADR MDR cells were (almost) completely reversed. The effects of these inhibitors on drug uptake were already apparent during the earliest measured time points (less than 15 s). Also, the enhanced efflux of daunorubicin from GLC4/ADR cells was inhibited. In ATP-depleted cells, the intracellular pH was lowered by approximately 0.3 units in resistant as well as in sensitive cells. The lower intracellular pH, however, could not account for the increase in daunorubicin accumulation in the resistant cells. Also, for vincristine and etoposide, the increases in drug accumulation under energy-deprived conditions were more pronounced in the resistant SW-1573/2R120 cells than in the parent SW-1573 cells. These results suggest that accumulation of drugs in the non-P-glycoprotein MDR human lung carcinoma cell lines SW-1573/2R120 and GLC4/ADR is reduced by an energy-dependent drug export mechanism which prevents efficient transport of drug to the target. Since P-glycoprotein expression in lung tumors is generally low, these MDR lung cancer cell lines can be used as a model to study alternative mechanisms leading to multidrug resistance in this tumor type.
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PMID:Energy-dependent processes involved in reduced drug accumulation in multidrug-resistant human lung cancer cell lines without P-glycoprotein expression. 130 22

The energy metabolism of an atypical multidrug resistant human small cell lung carcinoma cell line (GLC4/ADR) was studied. The glycolytic rate was 30% reduced and the glucose-6-phosphate dehydrogenase activity 2-fold increased in GLC4/ADR compared to the parental sensitive line (GLC4). Although mitochondrial respiration activities were similar in both cell lines, GLC4/ADR was more sensitive to the antimitochondrial drugs doxycycline and oligomycin, while cross-resistance was observed for the glycolytic inhibitor 2-deoxyglucose and for the antimitochondrial drug rhodamine-123. Continuous incubation with doxycycline induced a dramatic reduction of mitochondrial mRNAs in both cell lines, whereas a strong reduction of the nuclear-coded mRNA for subunit IV of cytochrome c oxidase was induced in GLC4/ADR only. Incubation with doxycycline had an additive effect on the cytotoxicity of adriamycin in both cell lines. Thus, a form of collateral sensitivity to antimitochondrial drugs may exist in atypical multidrug resistant cell lines.
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PMID:Increased sensitivity of an adriamycin-resistant human small cell lung carcinoma cell line to mitochondrial inhibitors. 131 Apr 1

Carmethizole hydrochloride [1-methyl-2-methylthio-4,5-bis(hydroxymethyl)imidazole-4', 5'-bis(N-methylcarbamate)hydrochloride, NSC 602,668; hereafter called carmethizole] is a new antitumor drug that has shown relatively broad activity in initial evaluations against several murine tumors and human tumor xenografts in vivo. The present studies were designed to address questions about carmethizole's activity against established disease, its activity on different treatment schedules, and the extent of its cross-resistance with established drugs. Human MX-1 mammary carcinoma, human NCI-H82 small-cell lung carcinoma, and human LOX amelanotic melanoma xenografts in athymic mice were used to determine the drug's activity against established disease; the NCI-H82 lung-tumor xenograft in athymic mice was used to explore its schedule dependence; and a series of drug-resistant murine leukemias provided an in vivo cross-resistance profile. When injected i.p., carmethizole exhibited antitumor activity against advanced-stage s.c. MX-1 mammary, s.c. NCI-H82 lung, and i.p. LOX melanoma xenografts and was as effective against established disease (MX-1 and LOX) as it was against early-stage disease (no data are available for early-stage NCI-H82). The therapeutic effect of carmethizole was not route-dependent, as was evidenced by the similar delays observed in tumor growth following i.p. and i.v. administration. The use of a split-dose schedule on a single day instead of one bolus injection yielded an increase in the total dose delivered, resulting in an increased delay in tumor growth. Murine leukemias resistant to vincristine (VCR), amsacrine (AMSA), or methotrexate (MTX) were not cross-resistant to carmethizole. However, murine leukemias resistant to doxorubicin (ADR), melphalan (L-PAM), cisplatin (DDPt), 1-beta-D-ara-binofuranosylcytosine (ara-C), and 5-fluorouracil (5-FU) were cross-resistant to carmethizole, suggesting that patients who have previously been treated with any of these agents might be less likely to respond to carmethizole than those who have had no opportunity to develop resistance to any of these compounds. We anticipate that the information derived from these studies may be useful in the design of clinical trials of carmethizole and may stimulate additional basic research on the mechanism of action of this new agent.
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PMID:Antitumor activity and cross-resistance of carmethizole hydrochloride in preclinical models in mice. 132 3

Cells exhibiting decreased topoisomerase II (Topo II) activity are resistant to several drugs that require Topo II as an intermediate. These drugs are cytotoxic due to the formation of a cleavable complex between the drug, Topo II and DNA. Fostriecin belongs to a new class of drugs that inhibit Topo II without inducing the formation of this cleavable complex. We tested fostriecin in three human small-cell lung carcinoma cell lines. GLC4 is the parent line. GLC4/ADR is the P-glycoprotein-negative multidrug-resistant subline, which is resistant to several Topo II inhibitors due to its decreased Topo II activity. GLC4/cDDP is the cisplatin-resistant subline, which displays increased Topo II activity. Topo II activity proved to be 100% in GLC4, 35% in GLC4/ADR and 130% in GLC4/cDDP. The fostriecin concentration causing inhibition of the growth of 50% of the cells (IC50) in the microculture tetrazolium assay following continuous incubation was 11.2, 4.1 and 14.9 microM, respectively. After 1-h incubations, the IC50 was 117.8, 101.3 and 219.8 microM, respectively. Our results indicate a relationship between Topo II activity and fostriecin sensitivity in these closely related cell lines. At least in vitro, fostriecin displayed the capacity to kill cells showing resistance to drugs due to decreased Topo II activity. There was no relationship between this capacity and an increase in the activity of the reduced-folate carrier system, the proposed mechanism for cellular entry of fostriecin, since we found no correlation between the cytotoxicity of fostriecin and that of methotrexate.
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PMID:Lack of cross-resistance to fostriecin in a human small-cell lung carcinoma cell line showing topoisomerase II-related drug resistance. 165 25

31P nuclear magnetic resonance (NMR) spectra of cells and of cell extract revealed high levels of phosphorylcholine (PC) and phosphocreatine (PCr) in an adriamycin-resistant human small cell lung carcinoma cell line (GLC4/ADR) and the adriamycin-sensitive parental cell line (GLC4). PCr levels in extracts of GLC4/ADR were increased compared to extracts of GLC4. We estimated that 11% of the total intracellular ATP is not bound to Mg2+ in both cell lines. This value corresponded to an intracellular free Mg2+ of 0.30 mM. The effects of different adriamycin concentrations, 0.05, 1 and 30 microM for GLC4 and 1, 30 and 200 microM for GLC4/ADR, on the phosphorus metabolite levels in continuously perfused cells were monitored. Significant differences between GLC4 and GLC4/ADR included: (a) a strong increase in the beta ATP level in the presence of 30 microM adriamycin in GLC4 only, followed by a fast decrease after 5 h of perfusion. (b) a less dramatic increase in the PC level in GLC4/ADR and an unchanged ATP level in the presence of increasing adriamycin concentrations. (c) an increased GPC level in GLC4/ADR in the presence of adriamycin. The changes in PC and GPC levels in the presence of adriamycin suggested that the phospholipid turnover was increased in GLC4/ADR and could be stimulated in the presence of adriamycin. In both cell lines, PCr levels decreased faster than the ATP levels after adriamycin treatment. Thus, biochemical markers for adriamycin resistance can be detected with NMR spectroscopy. However, more studies are necessary to obtain parameters to distinguish drug-sensitive from drug-resistant tumours in patients by NMR spectroscopy.
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PMID:NMR spectroscopy analysis of phosphorus metabolites and the effect of adriamycin on these metabolite levels in an adriamycin-sensitive and -resistant human small cell lung carcinoma cell line. 184 46

In a previous study we suggested that, in addition to the reduced Adriamycin accumulation, part of the resistance in an Adriamycin-resistant human small cell lung carcinoma cell line (GLC4/ADR) could be explained by supposing a changed Adriamycin-DNA-topoisomerase II (Topo II) interaction. The present study showed that the Mr 170,000 P-glycoprotein was not overexpressed in GLC4/ADR and that verapamil did not reverse the Adriamycin resistance. GLC4/ADR expressed cross-resistance to teniposide, etoposide, 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), and mitoxantrone. Further investigations of the drug-Topo II interaction revealed that the decatenation activity of Topo II was two- to threefold reduced in both cellular and nuclear extracts from GLC4/ADR. Topo I activities appeared similar in extracts from GLC4/ADR and the parental sensitive cell line (GLC4). The slight increase in doubling time from 15 to 18 h, while the cell cycle distribution remained unchanged, could not account for the reduced Topo II activity in GLC4/ADR. Etoposide and m-AMSA-induced DNA cleavage was 5-fold reduced in cellular extracts from GLC4/ADR. Inhibition of the decatenation activity of Topo II in the presence of VP-16 and m-AMSA was increased twofold in the cellular extracts from GLC4/ADR. Therefore, these results suggest that resistance of GLC4/ADR to Adriamycin was in part due to the reduced drug-induced formation of the cleavage complex.
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PMID:Reduced DNA topoisomerase II activity and drug-induced DNA cleavage activity in an adriamycin-resistant human small cell lung carcinoma cell line. 196 22

A series of derivatives of 9-anilinoacridine related to the anti-leukaemia agent amsacrine have been tested in continuous exposure growth inhibition assays to determine the degree of cross-resistance in the Adriamycin-resistant P/ADR murine leukaemia line. Measured IC50 values for the two cell lines were only poorly correlated (r = 0.51), and cross-resistance as measured by the ratio of IC50 values varied from 2-fold and 272-fold. A high degree of resistance was found to be associated with the presence of amino or substituted amino groups on the acridine ring system. Logarithmic IC50 values were determined for other cell lines (L1210 leukaemia, Lewis lung carcinoma and HCT-8 human colon carcinoma) and were compared with those for the P388 lines to determine the degree of linear correlation. HCT-8 values were strongly correlated with P/ADR values (r = 0.84) while L1210 values correlated strongly with those of the sensitive P388 line (r = 0.98). Values for Lewis lung cells showed an intermediate pattern and correlated with a linear combination of values for both P388 lines (r = 0.88). Examination of available IC50 values for a number of rodent and human cell lines indicates that their sensitivity patterns are either P388-like or else intermediate between P388 and P/ADR. The series of amsacrine derivatives may be useful in characterizing the nature and degree of multidrug-resistance in cultured cell lines.
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PMID:Relationship between the structure of analogues of amsacrine and their degree of cross-resistance to adriamycin-resistant P388 leukaemia cells. 335 8

A 76-year-old man with lung carcinoma, who was undergoing both radiotherapy and chemotherapy (CDDP + ADR) suddenly died with the onset of abdominal symptoms. Autopsy disclosed that the main cause of death was suppurative panperitonitis, caused by a perforation of a metastatic lesion at the jejunum. A histological examination revealed extensive tumor necrosis in the metastatic liver lesions as well as in the jejunal lesions. Neither inflammatory nor circulatory damage was observed in the perforated lesion. Therefore, the cause of this perforation was considered to be chemotherapy that had brought on tumor necrosis. No similar reports of lung cancer deaths have been found in the literature in which the microscopic details were described. Accordingly, this case is reported for future reference with regard to cancer chemotherapy.
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PMID:[An autopsied case of pulmonary carcinoma with perforation peritonitis due to metastatic tumor necrosis at the jejunum caused by chemotherapy]. 335 62

From April, 1979 to November, 1981, 293 patients with small cell lung carcinoma (SCLC) were entered on a randomized, controlled study comparing the two induction regimens of high-dose CAV (HD-CAV) (cyclophosphamide [CTX] 1200 mg/m2, doxorubicin [ADR] 70 mg/m2 and vincristine [VCR] 1 mg/m2 intravenously (IV) on days 1 and 21) versus, conventional-dose CAV + VP-16 (etoposide) (CAV-VP) (CTX 1000 mg/m2, ADR 40 mg/m2, VCR 1 mg/m2 IV on days 1 and 21 with VP-16 100 mg/m2 on days 1-3, and 21-23). Responding and stable patients were continued on conventional-dose CAV for 5 consolidation courses. Prophylactic brain irradiation delivered after the first consolidation course in responders was optional. Patients were included in the study if they had extensive disease (i.e., beyond one hemithorax), no prior chemotherapy, or radiotherapy and performance status of 50 or above. After 2 induction courses, 215 cases are evaluable. Of these, 76 of 106 (72%) patients treated with HD-CAV have responded (greater than 50% regression), including 13 complete responders (CRs) versus 80 of 108 (74%) patients on CAV-VP, including 15 CRs. Of the 130 evaluable patients who have completed consolidation (HD-CAV, 65; CAV-VP, 65), an additional 22 patients achieved CR (HD-CAV, 12; CAV-VP, 10) for an overall CR rate of 24%. Median duration of remission was 33.6 weeks for HD-CAV and 35.6 weeks for CAV-VP (P = 0.61). Median duration of complete response for HD-CAV was 33.8 weeks and for CAV-VP 36.7 weeks (P = 0.81). Survival curves were similar for the two regimens, with medians of 42.1 weeks for HD-CAV and 42.3 weeks for CAV-VP (P = 0.35). Survival correlated with performance status and quality of response. As anticipated, the major toxicity for both induction regimens was leukopenia. During induction, granulocyte nadirs of less than 500/mm3 occurred in 81% of patients on HD-CAV and 77% of patients on CAV-VP. Thus, dose intensification appears to produce high response rates and modest complete response rates in extensive SCLC, but it does not appear to improve materially survival compared to prior reports of conventional-dose therapy.
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PMID:Combination chemotherapy in small cell lung carcinoma. A randomized study of two intensive regimens. 609 79

A comparison of CTX + CCNU and CTX + CCNU + procarbazine as initial systemic treatment was made in 440 evaluable patients with small-cell carcinoma of the lung. The overall response rate for patients receiving the three-drug combination was 57% (11% CR) compared with 44% (9% CR) for the two-drug combination. Median survival times were similar, 27 (with procarbazine) and 29 weeks (without procarbazine). Nonresponders to the initial treatment received ADR, ADR + VCR, and ADR + VP-16 with overall response rates of 14% (2 of 14), 27% (9 of 33), and 30% (15 of 51), respectively. Median survivals for nonresponders, as measured from day 42, were 15 weeks (ADR), 21 weeks (ADR + VCR), and 22 weeks (ADR + VP-16). Responders to the initial treatment either continued on the initial therapy or received a non-cross-resistant combination chemotherapeutic regimen (ADR + VCR) alternating with the initial therapy. There is also the suggestion that responders who received the cycled therapy after day 42 survived significantly longer than responders who did not switch treatments until relapse, 38 vs. 29 weeks.
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PMID:Phase III study of CCNU, cyclophosphamide, adriamycin, vincristine, and VP-16 in small-cell carcinoma of the lung. 627 69


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