UMLS:C0684249 - FACTA Search

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Query: UMLS:C0684249 (lung carcinoma)
23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antitumor effects of the camptothecin (CPT) derivative CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin , were tested on human tumor xenografts in nude mice. CPT-11 showed antitumor activity higher than that of Adriamycin, 5-fluorouracil, or futraful, with little or no reduction of body weight being observed in the mice. The growth of colon adenocarcinoma Co-4 was significantly inhibited after a single i.v. injection of CPT-11 at 25, 50, or 100 mg/kg. The single i.v. injection was also significantly effective against mammary carcinoma MX-1 and gastric adenocarcinoma St-15. All of the mice bearing MX-1 tumors were cured by the administration of CPT-11 every 4 days for a total of three treatments at a total dose of 200 mg/kg given i.v. or of 400 mg/kg given p.o. Three i.v. or oral treatments were also effective against Co-4, St-15, gastric adenocarcinoma SC-6, and squamous-cell lung carcinoma QG-56. To achieve the same efficacy attained by i.v. injection, however, oral doses 2-4 times higher than the i.v. doses were required. When the total dose was fixed at 100 mg/kg, a triple i.v. injection was most effective, followed by a single i.v. injection and, finally daily p.o. administration for 10 days. Although SN-38 (7-ethyl-10-hydroxycamptothecin), a metabolite of CPT-11, showed much stronger cytotoxic activity in vitro than did CPT-11, its antitumor effects were similar, if not inferior, to those of CPT-11 in vivo at the same dose level. CPT-11 was converted into SN-38 by human tumors, but the sensitivity of these tumors to CPT-11 in vivo was independent of their ability to produce SN-38. These results suggest that CPT-11 may be clinically effective, depending on the schedule of administration, but that its effectiveness is not related to the ability of the tumor to produce SN-38.
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PMID:Antitumor activity of a camptothecin derivative, CPT-11, against human tumor xenografts in nude mice. 185 76

Irinotecan (CPT-11) is a semi-synthetic derivative of camptothecin currently in clinical trials. In vitro, CPT-11 presented preferential cytotoxicity toward some solid tumor cells (mouse colon 38 and pancreas 03; human pancreas MIA PaCa-2) as compared to leukemia cells (L1210), whereas SN-38, a metabolite of CPT-11, was not solid tumor selective. In vivo, schedule of administration studies in P388 leukemia and mammary adenocarcinoma 16/C (MA16/C) showed that CPT-11 was not markedly schedule dependent. In order to determine its spectrum of anticancer activity, CPT-11 was evaluated against a variety of mouse and human tumors. The end points used were total log cell kill (Lck) for solid tumors and increase in life span (% ILS) for leukemia. Intravenous CPT-11 was found highly active against both early and advanced stage pancreatic ductal adenocarcinoma 03 (P03), with 60% long-term survivors and 100% complete regressions, respectively. Other responsive tumors included: colon adenocarcinomas 38 and 51 (both 1.0 Lck); MA16/C (3.4 Lck); MA13/C (1.0 Lck); human Calc18 breast adenocarcinoma (2.8 Lck); Glasgow osteogenic sarcoma (1.8 Lck); Lewis lung carcinoma (1.4 Lck); B16 melanoma (1.4 Lck); P388 leukemia (170% ILS) and L1210 leukemia (64% ILS). Of interest, CPT-11 was active against tumors with acquired resistance to vincristine (P388/Vcr), to doxorubicin (P388/Dox) and to docetaxel (Calc18/TXT). CPT-11 was also found highly active after oral administration in mice bearing P03 and MA16/C tumors. Pharmacokinetic evaluations performed i.v. at the highest non-toxic dosage in mice bearing P03 tumors revealed CPT-11 peak plasma concentrations (Cmax) of 8.9 micrograms/ml and a terminal half-life of 0.6 h. The metabolite SN-38 plasma concentrations presented a Cmax of 1.6 micrograms/ml and a terminal half-life of 7.4 h. Although the CPT-11 tumor levels were similar to the plasma concentrations for early time points, drug levels decreased more slowly in the tumor compared to plasma (half-life, 5.0 h). SN-38 tumor levels reached concentrations in the range of 0.32-0.34 micrograms/g and decayed with a half-life of 6.9 h. No significant difference in plasma or tumor pharmacokinetics of either CPT-11 or SN-38 were noted after one or five daily i.v. injections. Overall, these data show that CPT-11 has good activity in experimental models, when administered both by the i.v. and the oral routes. Compared to humans, a similar schedule of administration independence was observed and similar CPT-11 levels could be reached at efficacious dosages although metabolite SN-38 levels were found higher in mice.
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PMID:Experimental antitumor activity and pharmacokinetics of the camptothecin analog irinotecan (CPT-11) in mice. 882 13

The effect of different temperatures (37-42.5 degrees C) on SN-38 (the active metabolite of CPT-11) cytotoxicity was examined in the human lung carcinoma cell lines H460 and Calu-6 as well as the murine fibrosarcoma cell line L929. The cytotoxicity of SN-38, determined by MTT cell survival assay, was significantly increased in each cell line in combination with 41.8 degrees C hyperthermia (x60-120 min); the combination of SN-38 with 40.5 degrees C and 42.5 degrees C, however, was unchanged compared to 37 degrees C. Determination of topoisomerase (Topo) I DNA cross-linking in Calu-6 cells and L929 cells after treatment with SN-38 showed the same temperature profile as seen in the cell-survival assays with increased Topo I DNA cross-linking after treatment with the combination of SN-38 and 41.8 degrees C hyperthermia and unchanged Topo I DNA cross-linking at 40.5 degrees C and 42.5 degrees C. To test the hypothesis that increased Topo I DNA cross-linking and SN-38 cytotoxicity at 41.8 degrees C is caused by hyperthermia-modulated changes in Topo I activity, catalytic activity of Topo I extracted from each cell line and of purified human Topo I was determined at 20-42.5 degrees C. Topo I activity was found to be gradually increased with rising temperatures, resulting in significantly higher activity at 41.8 degrees C compared to 37 degrees C; further increase of temperature past 41.8 degrees C decreased Topo I activity back to levels found at 37 degrees C. Our data are used to explain a series of events resulting in hyperthermic enhancement of Topo I DNA cross-linking and SN-38 cytotoxicity in combination with 41.8 degrees C hyperthermia via increased Topo I activity.
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PMID:Hyperthermic modulation of SN-38-induced topoisomerase I DNA cross-linking and SN-38 cytotoxicity through altered topoisomerase I activity. 993 39

Irinotecan hydrochloride (CPT-11) is a prodrug of SN-38, which is an active metabolite with antitumor activity and side toxicity. The activities of CPT-11 and SN-38 depend on the closed lactone ring form of SN-38. We have examined the tissue distributions of the closed and open forms of CPT-11 and SN-38 in Lewis lung carcinoma-bearing mice after the administration of liposomal CPT-11 (S-Lip) and polyethyleneglycol (PEG)-modified S-Lip (S-PEG). The plasma concentrations of closed CPT-11 and SN-38 were increased by liposomalization, and their blood circulation was prolonged by the PEG modification. The concentrations of closed CPT-11 and SN-38 in tumors were elevated by both the liposomalization and PEG modification. The closed/total ratio of SN-38 in the tumors of the S-PEG group was greater than that of the CPT-11 solution (Sol) group. Thus, SN-38 was thought to be generated in intact liposomes containing CPT-11. The bile concentration of closed SN-38, which is responsible for CPT-11-induced intestinal disorder, was decreased by liposomalization. In an in vitro experiment, the SN-38/CPT-11 ratio in the tumor cells of the S-Lip group was found to be higher than that of the Sol group, and the ratio of the closed form of SN-38 was increased by the liposomalization. Laser scanning confocal microscopy showed the generation of SN-38 in the liposomal membrane after the incubation of S-Lip with carboxylesterase. It is therefore considered that a part of CPT-11 is converted to SN-38 in the intact liposomes.
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PMID:Effective irinotecan (CPT-11)-containing liposomes: intraliposomal conversion to the active metabolite SN-38. 1018 94

Activation of signaling pathways after DNA damage induced by topoisomerase (topo) poisons can lead to cell death by apoptosis. Treatment of human nonsmall cell lung carcinoma (NSCLC-3 or NSCLC-5) cells with the topo I poison SN-38 or the topo II poison etoposide (VP-16) leads to activation of NF-kappaB before induction of apoptosis. Inhibiting the degradation of IkappaBalpha by pretreatment with the proteasome inhibitor MG-132 significantly inhibited NF-kappaB activation and apoptosis but not DNA damage induced by SN-38 or VP-16. Transfection of NSCLC-3 or NSCLC-5 cells with dominant negative mutant IkappaBalpha (mIkappaBalpha) inhibited SN-38 or VP-16 induced transcription and DNA binding activity of NF-kappaB without altering drug-induced apoptosis. Regulation of apoptosis by mitochondrial release of cytochrome c and activation of pro-caspase 9 followed by cleavage of poly(ADP-ribose) polymerase by effector caspases 3 and 7 was similar in neo and mIkappaBalpha cells treated with SN-38 or VP-16. In contrast to pretreatment with MG-132, exposure to MG-132 after SN-38 or VP-16 treatment of neo or mIkappaBalpha cells decreased cell cycle arrest in the S/G2 + M fraction and enhanced apoptosis compared with drug alone. In summary, apoptosis induced by topoisomerase poisons in NSCLC cells is not mediated by NF-kappaB but can be manipulated by proteasome inhibitors.
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PMID:Roles of NF-kappaB and 26 S proteasome in apoptotic cell death induced by topoisomerase I and II poisons in human nonsmall cell lung carcinoma. 1111 10

Integration of chemotherapy and radiation is the standard practice in the management of locally advanced inoperable NSCLC. To assess the biological interaction between third generation chemotherapeutic agents and radiation in non-small cell lung cancer (NSCLC) in vitro, we tested a number of different drugs (paclitaxel, docetaxel, gemcitabine, topotecan, SN-38 and cisplatin) combined with radiation, in lung cancer cell lines. Cellular chemosensitivity was determined, using the semi-automated colorimetric MTT assay, after 48, 72 and 96 h of exposure to increasing drug concentrations, (0.001-100 microM) and radiation doses (100-400 cGy). Cell lines used were the adenocarcinoma (ADK), A-549, and the squamous-cell carcinoma (SCC), LX-1. Cells were pre-treated with anticancer agents at 24, 12 and 0 h before irradiation. Cytofluorimetric cell cycle analysis was performed. A significant S-phase block or a G(2)/M block was seen with gemcitabine and topotecan or paclitaxel pre-treatment, respectively. Apoptosis was seen only after paclitaxel exposure in the A-549 cell line. Despite a similar pattern of cell-kinetic changes induced by chemotherapy pre-treatment in all cell lines, the adenocarcinoma A-549 cell line was not radiosensitized by any of the anticancer agents tested, whereas synergism was observed in the LX-1 squamous carcinoma cell line, when exposed to gemcitabine, SN-38, topotecan and cisplatin. Paclitaxel, despite a favourable cell cycle effect, was not found to be synergistic with radiotherapy in our experimental model. In conclusion, the observed synergism appears to be dose- and timing-independent and seems to be related to the histological subtype being present in SCC only. Favourable perturbation of the cell cycle is evident with all the new agents tested in both cell types, but was not sufficient to produce synergism with radiation.
Lung Cancer 2001 Jul
PMID:Interaction between novel anticancer agents and radiation in non-small cell lung cancer cell lines. 1142 93

Overexpression of breast cancer resistance protein (BCRP) ABCG2 reportedly confers cancer cell resistance to camptothecin-based anticancer drugs, such as topotecan and 7-ethyl-10-hydroxycamptothecin (SN-38: the active metabolite of irinotecan). We have recently shown that SN-38-selected PC-6/SN2-5H human lung carcinoma cells overexpressed BCRP with the reduced intracellular accumulation of SN-38 and SN-38-glucuronide (S. Kawabata et al., Biochem. Biophys. Res. Commun. 280, 1216-1223, 2001). In the present study, we have examined whether BCRP transports SN-38 and/or SN-38-glucuronide in vitro, by using plasma membrane vesicles from the parental PC-6 and resistant PC-6/SN2-5H cells, where SN-38 and SN-38-glucuronide accumulation in membrane vesicles was measured by HPLC. Both SN-38 and SN-38-glucuronide were ATP-dependently transported into membrane vesicles prepared from PC-6/SN2-5H cells, whereas no transport activity was observed in membrane vesicles from PC-6 cells. The kinetic parameters of the transport observed in PC-6/SN2-5H vesicles were K(m) = 4.0 microM, V(max) = 714 pmol/mg/min for SN-38 and K(m) = 26 microM, V(max) = 833 pmol/mg/min for SN-38-glucuronide. These findings suggest that BCRP expressed in PC-6/SN2-5H cells transports both SN-38 and SN-38-glucuronide with a higher affinity toward SN-38.
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PMID:Transport of 7-ethyl-10-hydroxycamptothecin (SN-38) by breast cancer resistance protein ABCG2 in human lung cancer cells. 1168 82

The anticancer agent irinotecan (CPT-11) is a prodrug converted to its active form, SN-38, by human carboxylesterase (hCE) and the SN-38 is further metabolized to its inactive form, SN-38G. We investigated the expression of hCE in human lung cancer cells as well as the ability of these cells to convert CPT-11 to SN-38 using surgically resected tumor samples and cultured cell lines. SN-38 was 40- to 3,000-fold more toxic to lung cancer cell lines than CPT-11, which acted more time-dependently than SN-38. Although human lung cancer cells expressed hCE in the cytoplasm, hCE expression levels in cancer cells were not correlated with their drug sensitivities. Although intracellular CPT-11 and SN-38 levels continuously increased within 60 min of CPT-11 exposure, SN-38 levels in cells exposed to SN-38 decreased. Cells with the ability to metabolize SN-38 to SN-38G were more resistant to extracellular SN-38 than cells lacking the ability. Of 25 squamous cell carcinomas, 15 were strongly positive for hCE and six were negative. Of 25 adenocarcinomas, four were strongly positive for hCE and 16 were positive, while five were negative. Thus, 70% of non-small cell lung cancers expressed hCE. From these results, we conclude that human lung cancer cells expressed the enzyme which can convert CPT-11 to SN-38 and that intracellular SN-38 converted from CPT-11 may act as a chemotherapeutic agent together with SN-38 absorbed from the outside and augment the dose intensity of SN-38. Therefore, to assess the effects of CPT-11 prior to chemotherapy, it is important to check if lung cancer cells express hCE.
Lung Cancer 2003 Aug
PMID:Intracellular conversion of irinotecan to its active form, SN-38, by native carboxylesterase in human non-small cell lung cancer. 1287 82

Accumulating evidence suggests that several ATP-binding cassette (ABC) transporters mediate the elimination of anticancer drugs from cancer cells and thereby confer drug resistance. SN-38-selected PC-6/SN2-5H human lung carcinoma cells were shown to overexpress ABCG2 with the reduced intracellular accumulation of SN-38, the active metabolite of irinotecan. We have recently demonstrated that plasma membrane vesicles prepared from those cells transported SN-38 in an ATP-dependent manner, and it was suggested that ABCG2 is involved in the active extrusion of SN-38 from cancer cells. In the present study, we have cloned the cDNA of ABCG2 from PC-6/SN2-5H human lung carcinoma cells, expressed ABCG2 in Sf9 insect cells, and characterized its function. Sequence analysis has revealed that the cloned ABCG2 has an arginine at the amino acid position 482, as does the wild type. Expression of the cloned ABCG2 in Sf9 cell membranes was detected by immunoblotting with the BXP-21 antibody. Contrary to our expectation, however, ATPase activity in the cell membranes expressing ABCG2 was stimulated by neither SN-38 nor rhodamine 123. It is suggested that there is a partner protein of ABCG2 required for heterodimer formation to exhibit transport activity toward SN-38.
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PMID:Does ABCG2 need a heterodimer partner? Expression and functional evaluation of ABCG2 (Arg 482)*. 1561 61

EGFR mutations are a major determinant of lung tumor response to gefitinib, an EGFR-specific tyrosine kinase inhibitor. Obtaining a response from lung tumors expressing wild-type EGFR is a major obstacle. The combination of gefitinib and cytotoxic drugs is one strategy against lung cancers expressing wild-type EGFR. The DNA topoisomerase inhibitor irinotecan sulfate (CPT-11) is active against lung cancer. We examined the sensitivity of lung cancers expressing wild- or mutant-type EGFR to the combination of gefitinib and CPT-11. The in vitro effect of gefitinib and SN-38 (the active metabolite of CPT-11) was examined in seven lung cancer cell lines using the dye formation assay with a combination index. When administered concurrently, gefitinib and SN-38 had a synergistic effect in five of the seven cell lines expressing wild-type EGFR, whereas the combination was antagonistic in PC-9 cells and a PC-9 subline resistant to gefitinib and expressing deletional mutant EGFR (PC-9/ZD). When administered sequentially, treatment with SN-38 followed by gefitinib had remarkable synergistic effects in the PC-9 and PC-9/ZD cells. In an in vivo tumor-bearing model, this combination had a schedule-dependent synergistic effect in the PC-9 and PC-9/ZD cells. An immunohistochemical analysis of the tumors in mice treated with CPT-11 and gefitinib demonstrated that the number of Ki-67 positive tumor cells induced by CPT-11 treatment was decreased when CPT-11 was administered in combination with gefitinib. In conclusion, the sequential combination of CPT-11 and gefitinib is considered to be active against lung cancer.
Lung Cancer 2006 Jul
PMID:Effects of different combinations of gefitinib and irinotecan in lung cancer cell lines expressing wild or deletional EGFR. 1671 12

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