Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CPT-11, a recently developed topoisomerase I (Topo I) inhibitor, attracts the attention not only of basic researchers but also of clinicians because of its high antitumor activity. The CPT-11 resistant human lung cancer cell line, PC-7/CPT, showed 10-fold resistance compared to parental cell line, PC-7. The total activity of Topo I in the resistant cell line was one fourth that of the parental sensitive cell line. The Topo I from the resistant cells was also 5-fold more resistant to the inhibitory effect of CPT-11 than that of the parental cells. We speculated that the alteration of the Topo I gene may be responsible for the change in topoisomerase activity of the CPT-11 resistant cell line. Therefore, we analyzed the mutation of Topo I gene using the method of single strand conformation polymorphism of polymerase chain reaction and the reverse transcriptase. We divided Topo I cDNA into ten fragments which overlapped each other and covered whole coding sequences of the Topo I cDNA. We observed mobility shift of two fragments in the PC-7/CPT, suggesting the presence of some mutations in these fragments. We performed the direct-sequencing of these portions by the dideoxy chain termination method and observed an altered sequence having a G to A base change in PC-7/CPT. This base substitution results in replacement of the conserved threonine at 729 position with alanine. These results suggest that the point mutation of Topo I gene is related to the decreases of Topo I activity and the sensitivity to Topo I inhibitor in PC-7/CPT cells.
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PMID:Detection of topoisomerase I gene point mutation in CPT-11 resistant lung cancer cell line. 133 3

To determine whether there exists cross-resistance between anticancer drugs and radiation, six drug-resistant human lung cancer cell lines and their parental cell lines were examined for radiosensitivity using a growth-inhibition assay. Only one cisplatin-resistant cell line, PC-9/CDDP, showed cross-resistance to radiation. The other three cisplatin-resistant cell lines (PC-7/CDDP, PC-4/CDDP, and H69/CDDP), an etoposide-resistant cell line (H69/VP) and a camptothecin-resistant cell line (PC-7/CPT) did not show cross-resistance to radiation. To analyze the mechanism of radiation resistance in PC-9/CDDP cells, the formation and repair of radiation-induced DNA single-strand breaks (ssb) and double-strand breaks (dsb) were examined by alkaline elution and neutral elution respectively. Although the formation of DNA ssb and repair of both DNA ssb and DNA dsb were the same for both cell lines, the formation of DNA dsb in PC-9/CDDP cells was significantly less than those in PC-9 cells. Measurement of intracellular glutathione content in all of the cell lines revealed that only PC-9/CDDP cells had a significant increase of glutathione content compared to the parental cells. Buthionine sulfoximine treatment of PC-9/CDDP cells caused an increase of DNA dsb to the same levels as in PC-9 cells after irradiation and caused a complete radiosensitization. These results indicate that cross-resistance to radiation in drug-resistant cells in a rare phenomenon, and increased glutathione content may play a crucial role in the emergence of cross-resistance to radiation in the drug-resistant cells.
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PMID:Radiation sensitivities in various anticancer-drug-resistant human lung cancer cell lines and mechanism of radiation cross-resistance in a cisplatin-resistant cell line. 140 May 62

Although glucuronidation catalyzed by uridine 5'-diphosphoglucuronosyltransferase (UGT) is a major pathway of drug inactivation in humans, glucuronidation in malignant cells has received little attention as a cause of anti-cancer drug resistance. In this study, we tried to elucidate the role of SN-38 glucuronidation in the CPT-11-resistant human lung cancer cell line PC-7/CPT. PC-7/CPT cells possessed an increased activity to glucuronidate SN-38 compared to the parent cells, PC-7. Furthermore, sensitivity of PC-7/CPT cells to SN-38 was improved by inhibiting UGT activity. Western and northern blot analyses demonstrated that this increased activity was due to increased levels of UGT protein and mRNA. These results not only imply that upregulation of UGT activity in PC-7/CPT cells may contribute in part to SN-38 resistance, but also illustrate the important of drug metabolism within malignant cells themselves, as a cause of drug resistance.
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PMID:The role of glucuronidation in 7-ethyl-10-hydroxycamptothecin resistance in vitro. 947 40

Lung cancer represents the leading cause of cancer mortality. Non-small cell lung cancer (NSCLC) accounts for about 75% to 80% of lung cancer cases and carries a 5-year survival of about 10% to 15% for all stages. Approximately one third of NSCLC patients present with stage III disease, which is defined as locally advanced tumour confined to the chest without distant metastasis. The traditional treatment for stage III patients has been thoracic radiotherapy (RT). However, the impact of thoracic RT alone has been minimal with published studies showing median survival < 1 year and 5-year survival of 5% to 7%. Thus, the treatment of stage III NSCLC remains a significant challenge. The metastatic nature of this disease has been responsible for the poor survival statistics and emphasises the need for effective systemic treatment. In recent years, cisplatin-containing combination chemotherapy has emerged as a viable option in the treatment of NSCLC. Combined modality therapy employing systemic (chemotherapy) and local (RT with or without surgery) approaches has shown favourable results in patients with stage III disease. Randomised studies have demonstrated the benefit of concurrent or sequential chemoradiation in selected patients with a good performance status and minimal weight loss. The exact sequence has yet to be determined. Moreover, randomised studies in stage IIIA potentially resectable disease show survival advantage for patients receiving combined modality treatment. Thus, combined modality treatment has the potential to improve overall survival by increasing both local and distal control. These recent reports of randomised clinical trials of combined modality therapy for stage III NSCLC form the basis for this report. Several new agents, like the taxanes, CPT-II and gemcitabine show promising activity in NSCLC treatment. Ongoing studies are evaluating the potential role of these new agents in combined modality treatment but since the phase III trials have not been reported yet these studies will not be discussed.
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PMID:Combined modality therapy of non-small cell lung cancers. 1067 59

Among the numerous clinical regimens used in combination chemotherapy, synergy is particularly marked in combinations containing cisplatin (CDDP). However, the clinical use of CDDP is sometimes limited due to its nephrotoxicity. Nedaplatin (NDP) is a second-generation platinum complex with reduced nephrotoxicity that may substitute for CDDP or even surpass it for use in combination with other drugs. We investigated the effects of combinations of NDP and other anticancer drugs on the growth of human small cell lung cancer cells (SBC-3) and non-small cell lung cancer cells (PC-14) using a three-dimensional analysis model. Among the combinations tested, the combination of NDP and irinotecan (CPT-11) showed the most marked synergistic interaction, and the synergism has also been observed against PC-14 cells. With regard to treatment schedule, a remarkable synergistic interaction was produced by concurrent exposure to NDP and CPT-11. On the other hand, sequential exposure to the two drugs led only to additivity. To analyze the interaction between the drugs, the effect of NDP on the 7-ethyl-1-hydroxy-CPT (the active form of CPT-11)-induced inhibitory effect on DNA topoisomerase I was examined. The topoisomerase I-inhibitory effect of 7-ethyl-1-hydroxy-CPT was enhanced 10-fold in the presence of NDP at microgram/milliliter concentrations. These biochemical interactions might be responsible for the synergistic interaction between NDP and CPT-11. These results suggest that the combination of NDP with CPT-11 may be clinically useful for the chemotherapy of lung cancer.
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PMID:In vitro synergistic interactions between the cisplatin analogue nedaplatin and the DNA topoisomerase I inhibitor irinotecan and the mechanism of this interaction. 1120 10

7-ethyl-10-[4-(1-piperidyl)-1-piperidyl] carbonyloxy-camptothecin, a topoisomerase I (topo I) inhibitor, is one of the most active agent against lung cancer, and its radiosensitizing effect has been reported recently. We evaluated a combination in vitro effect of irradiation and 7-ethyl-10-hydroxy-CPT (SN-38), an active metabolite of 7-ethyl-10-[4- (1-piperidyl)-1-piperidyl] carbonyloxy-camptothecin, on a human small cell lung cancer cell line (SBC-3) and its cisplatin-resistant subline (SBC-3/CDDP). Growth-inhibitory effects of irradiation with or without SN-38 were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. A modified isobologram method was used to evaluate the treatment interaction. The combination of irradiation and SN-38 showed a synergistic inhibitory effect on the growth of SBC-3/CDDP despite its cross-resistance to irradiation and SN-38. In contrast, the same combination showed only an additive effect on the growth of parental SBC-3 cells. There was no significant difference in topo I protein expression between these two cell lines. In SBC-3 cells, topo I catalytic activity was suppressed by 4 Gy of irradiation, without a decrease of nuclear topo I protein, whereas the exposure of SBC-3 cells to 1 microM SN-38 subsequent to irradiation showed no remarkable additional effects on both topo I activity and protein content. On the other hand, in SBC-3/CDDP cells, topo I activity was unchanged by irradiation, but the subsequent exposure to SN-38 gave rise to a decrease in topo I activity, which was accompanied by a significant decrease in the topo I protein content (P = 0.02). These observations may indicate that SN-38 induces sequestration of topo I onto DNA in radiation-treated SBC-3/CDDP cells and suggest that the synergistic effect of irradiation and SN-38 in SBC-3/CDDP cells was considered attributable to DNA repair-related enhanced recruitment of topo I onto the damaged DNA.
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PMID:Synergistic effects of topoisomerase I inhibitor, 7-ethyl-10-hydroxycamptothecin, and irradiation in a cisplatin-resistant human small cell lung cancer cell line. 1180 71

Reverse transcription polymerase chain reaction (RT-PCR) single-strand conformation polymorphism analysis was used to detect topoisomerase I (top1) mutations in total RNA from 16 specimens that were excised during surgery from eight patients with non-small cell lung cancer (NSCLC) who had received preoperative chemotherapy consisting of irinotecan (CPT-11) and cisplatin. PCR single-strand conformation polymorphism and subsequent DNA sequencing analysis showed two nucleotide substitutions resulting in Trp736stop (TGG to TGA) and Gly737Ser (GGT to AGT) in one tumor specimen. The mutations were located near a site in top1 that was previously reported to harbor a mutation in the human lung cancer cell line PC7/CPT, which was selected for CPT resistance. These results demonstrate that mutations in top1 occur after chemotherapy with CPT-11 in NSCLC patients and suggest that development of resistance to CPT-11 in some patients may involve mutation of top1. However, the significance of top1 mutations to CPT resistance needs to be further investigated.
Lung Cancer 2002 Mar
PMID:Point mutations in the topoisomerase I gene in patients with non-small cell lung cancer treated with irinotecan. 1184 5

Lung cancer remains the primary cause of cancer-related death in both men and women in the United States. Chemotherapy has been shown to provide a survival benefit in patients with advanced non-small-cell lung cancer (NSCLC), and current regimens have produced median survivals of approximately 8 months and 1-year survival rates of 30% to 35% in patients with stage IIIB and IVdisease. Nevertheless, there remains room for improvement. Irinotecan (CPT-II, Camptosar) has demonstrated efficacy in the treatment of small-cell lung cancer (SCLC). It also appears to have promising activity in advanced NSCLC, producing overall response rates of up to 32%. Combinations of irinotecan and cisplatin or carboplatin (Paraplatin) have resulted in overall response rates of 25% to 56% in phase II and III studies in patients with advanced disease, with median survivals ranging from 9 to 13 months and 1-year survival rates of 33% to 58%. Current irinotecan-based doublet and triplet regimens appear to produce promising response rates with manageable toxicities. In addition, irinotecan has demonstrated potential as a radiosensitizing agent and is currently being evaluated in several trials of combined-modality therapy in patients with locally advanced NSCLC. Early trials of irinotecan in combination with cisplatin or carboplatin along with radiation therapy have reported overall response rates of 60% to 67%. The approach appears to have potential and warrants further study.
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PMID:Current role of irinotecan in the treatment of non-small-cell lung cancer. 1238 Sep 45

Small-cell lung cancer (SCLC) accounts for approximately 15% of all cases of lung cancer and is a particularly aggressive form of lung cancer characterised by a poor prognosis, rapid tumour growth, and early metastasis. Roughly, two-thirds of patients with SCLC present with extensive disease (ED) and one-third with limited disease (LD). Combination chemotherapy is the most effective treatment modality for SCLC, and several new agents, including carboplatin, ifosfamide, taxans, and topotecan, have been demonstrated to be active; however, there are no data on the survival benefit of these drugs. A CPT-11+ cisplatin regimen has shown improvement in overall survival over the global gold standard regimen, etoposide + cisplatin (Japanese Clinical Oncology Group: JCOG 9511), and three confirmatory randomised controlled trials are in progress to determine the reproducibility of the JCOG 9511 study. JCOG is evaluating the role of CPT-11 and a new triplet regimen containing CPT-11 in limited-stage SCLC. Strategies and the current protocols of the JCOG are presented and discussed. In the future, it will be essential to evaluate molecular target-based drugs for LD and ED SCLC with new standard combination chemotherapy regimens that include CPT-11.
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PMID:Progress in treatment of small-cell lung cancer: role of CPT-11. 1467 91

The role of non-platinum combination chemotherapy in the treatment of advanced non-small-cell lung cancer (NSCLC) has not yet been clarified. In this phase I study, the dose-limiting toxicity (DLT), the maximum tolerable dose (MTD) and the antitumor activity of a two-drug combination of docetaxel (DCT) and irinotecan (CPT) in patients with advanced NSCLC were evaluated. Previously untreated patients with NSCLC in stage IIIB with malignant pleural effusion or stage IV were eligible. Both drugs were administered by 1-h intravenous infusion on day 1, and repeated every 3 weeks. DCT was given before CPT administration. Five escalating dose levels of DCT/CPT (40/135, 50/135, 50/150, 60/150, and 60/165 mg/m2) were studied. Eighteen patients received 44 courses. The DLT was considered to be neutropenia, because grade 4 neutropenia lasting for 3 days or more was observed in three patients, which was accompanied with three episodes of febrile neutropenia. As a non-hematological toxicity, grade 3 diarrhea occurred in three patients. Since all the three patients treated at the fifth dose level (DCT at 60 mg/m2 and CPT at 165 mg/m2) experienced DLT (grade 4 neutropenia in two patients and grade 3 hepatic toxicity in one), this dose level was determined to be the MTD. The objective response rate was 33.3%, and the median survival time was 13.6 months. To confirm the effectiveness of this combination for advanced NSCLC which was suggested in the present study, a phase II study with the recommended doses (150 mg/m2 for CPT and 50-60 mg/m2 for DCT) is warranted.
Lung Cancer 2004 Jul
PMID:Phase I study of docetaxel and irinotecan in patients with advanced non-small-cell lung cancer. 1519 38


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