Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: KEGG:D01061 (CPT-11)
 1,899 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CPT-11 and Topotecan are a new semisynthetic derivative of CPT, and have been shown to inhibit DNA topoisomerase I and to have a strong antitumor activity with low toxicity against murine tumor. On the other hard, the new antitumor compounds, NC-190 and IST-622 have been shown to inhibit DNA topoisomerase II, and the clinical study are currently under progress. A phase II study of CPT-11 demonstrated that CPT-11 was a very active agent which a acceptable toxicities against patient with advanced non-small cell lung cancer and small cell lung cancer.
 ...
PMID:[DNA topoisomerase inhibitor]. 133 23

CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy camptothecin, is a well-known DNA topoisomerase I inhibitor. SN-38 is a metabolite of this compound. Both emit fluorescence when activated by a laser beam. With a confocal laser scanning microscope (CLSM), we determined the intracellular distribution of CPT-11 and SN-38 and the chronological changes in drug-treated PC-7, a cell line of human non-small cell lung cancer, and its CPT-11 resistant variant, PC-7/CPT cells. There were many more granules in the cytoplasm in PC-7/CPT than in the parent cell line (PC-7). The granule formation of the resistant cell could indicate a different drug metabolism in the cytoplasm from that of the parent cell. This technique would provide a new way of investigating the mechanism of resistance of cancer cells to anticancer drugs.
 ...
PMID:Intracellular distribution of CPT-11 in CPT-11-resistant cells with confocal laser scanning microscopy. 133 95

We established a cisplatin-resistant human ovarian cancer cell line (HAC2/0.1) from the parent cell line (HAC2/P) by continuous exposure of HAC2/P to 0.1 microgram of cisplatin/ml. Drug sensitivity determined by colony assay revealed that HAC2/0.1 was 2.4 times as resistant to cisplatin as the parental cell line. HAC2/0.1 was 12.1 and 2.0 times as resistant to (4s)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)-carbony loxy]dione hydrochloride trithydrate (CPT-11) and 7-ethyl-10-hydroxy-CPT (SN-38; an active metabolite of CPT-11), respectively, than HAC2/P. We studied the mechanism of cross-resistance to CPT-11 in HAC2/0.1. The glutathione (GSH) content was higher in HAC2/0.1 than in HAC2/P. The activity of DNA topoisomerase I and the accumulation of CPT-11 and SN-38 were also the same. On the other hand, the conversion of CPT-11 to SN-38 in HAC2/0.1 was about 3-fold less than in HAC2/P. Treatment of the parent and resistant cell lines with buthionine sulfoxamine (BSO) decreased the GSH content of both cell lines and decreased the 50% inhibitory concentrations of all the tested drugs for HAC2/0.1. The accumulation of CPT-11 in HAC2/0.1 but not in HAC2/P was increased by BSO treatment. On the other hand, in HAC2/P the 50% inhibitory concentrations of SN-38 and CPT-11 were not influenced by BSO treatment. The 50% inhibitory concentration of CPT-11 for HAC2/0.1 was not reduced by BSO treatment to the level for HAC2/P, even though the GSH content had been reduced more than in HAC2/P. These results show that there is no clear relationship between GSH and resistance to CPT-11. The decreased conversion of CPT-11 to SN-38 is considered to be the main cause of resistance to CPT-11 in this cell line.
 ...
PMID:Mechanism of cross-resistance to a camptothecin analogue (CPT-11) in a human ovarian cancer cell line selected by cisplatin. 134 10

CPT-11, a derivative of camptothecin, has drawn attention to cancer chemotherapy because of the specific mode of action, and the clinical study is now under progress. Liu et al. proved that camptothecin was a DNA topoisomerase I inhibitor, and some kinds of antitumor agents have been recognized as DNA topoisomerase II inhibitors. Based on these findings, DNA topoisomerases have emerged as target enzymes of antitumor agents in cancer chemotherapy. This paper dealt with investigation on the cytotoxic effects induced by combined use of DNA topoisomerase targeting antitumor agents, especially using CPT-11 as a core antitumor agent. Synchronous administration of CPT-11 with other antitumor agents induced cytotoxic effects less than metachronous administration of CPT-11 with other antitumor agents, especially preceding use of CPT-11. Dose of antitumor agents was not necessarily correlated to the cytotoxic effects. In some instances, small doses of the agents showed better therapeutic effects than large doses. The cytotoxic effects of vincristine, vindesine, and hydroxyurea were reduced by combination with CPT-11. On the other hand, non-cytotoxic agents such as aphidicolin, novobiocin, propentofylline, pentoxifylline, norfloxacin, and tosufloxacin enhanced the cytotoxic effects of CPT-11. Hypothetical consideration of cell killing and acquisition of drug resistance was proposed.
 ...
PMID:[Combination cancer chemotherapy using a DNA topoisomerase inhibitor CPT-11, as a core agent--the in vitro evaluation]. 165 82

The mechanisms of acquired resistance to mammalian DNA topoisomerase I inhibitor, camptothecin or its derivative (CPT-11) were described. Tumor cell lines containing altered or reduced topoisomerase I were reviewed. It might be necessary to further study on reduced inhibitor uptake and other unknown mechanism.
 ...
PMID:[Mechanisms of acquired resistance to DNA topoisomerase I inhibitors]. 165 83

CPT-11 is a semisynthesized derivative of camptothecin that has a potent antitumor activity by inhibiting DNA topoisomerase I. Leukopenia (mainly neutropenia) is DLF (dose limiting factor) and MTD (maximum tolerated dose) is higher than 250 mg/m2 in CPT-11 from the results of clinical phase I study. Now we are going on phase II study of CPT-11. We are seeing the cases responded to the drug in cancer of the lung, ovary, uterus, stomach, colorectum, pancreas, breast, malignant lymphoma etc.
 ...
PMID:[DNA topoisomerase inhibitor as chemotherapeutic drug--clinical point of view]. 165 85

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) is a novel camptothecin derivative that has been selected for clinical evaluation because of its broad spectrum of antitumor activity in animal models and its unique inhibitory effects on mammalian DNA topoisomerase I. Seventeen patients with advanced non-small-cell lung cancer were treated with CPT-11 at weekly dose levels ranging from 50 to 150 mg/m2. At least three weekly doses were given to all patients except four, and a total of 74 weekly doses were given to the 17 patients. The dose-limiting toxic effects were myelosuppression (predominantly leukopenia) and unpredictable diarrhea. Gastrointestinal toxic effects were severe and not well controlled by standard therapy in some patients. Interpatient variability of toxic effects was substantial (including two deaths) and did not correlate with the pharmacokinetic parameters of CPT-11 and 7-ethyl-10-hydroxycamptothecin, its major metabolite. Two previously untreated patients, who received doses of 100 and 125 mg/m2, had partial responses lasting 3.2 and 4.0 months, respectively. The maximum tolerated dose on this schedule was 100 mg/m2, which we also recommend as a starting dose for phase II studies. This schedule appears to allow a CPT-11 dose intensity which is double the dose intensity possible on a once-a-month schedule. However, careful supervision to assess gastrointestinal toxic effects and myelosuppression is indispensable because of wide individual differences in drug tolerance.
 ...
PMID:Phase I study of weekly intravenous infusions of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer. 165 62

Collateral drug sensitivity was induced in CPT-11-resistant cell lines (CPT-K and T). Ten of the 19 kinds of antineoplastic agents (especially, 5 of 6 kinds of DNA topoisomerase II inhibiting agents) were effective in inducing collateral drug sensitivity. Alteration of DNA topoisomerase I seemed to be unrelated to acquisition of multidrug resistance.
 ...
PMID:Collateral drug sensitivity induced in CPT-11 (a novel derivative of camptothecin)-resistant cell lines. 216 67

DNA topoisomerase I (topo I) has been identified as a principal target of a plant alkaloid camptothecin (CPT) and its derivative (CPT-11). The latter compound is expected to be a clinically useful antitumor agent. Three human tumor cell lines resistant to CPT (A549/CPT, HT-29/CPT, St-4/CPT) were isolated in vitro, and a murine tumor cell line resistant to CPT-11 (P388/CPT) was isolated in vivo by continuous exposure of the drugs. A549/CPT, HT-29/CPT, and St-4/CPT showed 1.8-, 6.9-, and 8.8-fold more resistance to CPT, and P388/CPT showed 45-fold more resistance to CPT than did the parental line. To examine the possible involvement of topo I in drug-resistant mechanisms, a monoclonal antibody was developed by using purified human topo I as antigen. The antibody T14C (immunoglobulin G1) recognized both human and murine topo I, as shown by Western blot analysis. By using this monoclonal antibody, cellular contents of topo I were examined in CPT-resistant tumor lines. Respective contents of topo I in HT-29/CPT, St-4/CPT, and P388/CPT were approximately 8-, 4-, and 3-fold less than those in their parental cell lines. A549/CPT, a weak CPT-resistant line, possessed amounts of topo I similar to those of the parental line. HT-29/CPT showed lower topo I activity than did the parental HT-29 in the nuclear extracts and in the hydroxylapatite column-eluted fractions. Purified topo I from HT-29 and HT-29/CPT showed similar catalytic activity when the same amounts of protein were used. These results indicate that the quantitative reduction of topo I content seems to be the most frequently occurring event in the development of resistance to camptothecin.
 ...
PMID:Decreased expression of DNA topoisomerase I in camptothecin-resistant tumor cell lines as determined by a monoclonal antibody. 217 10

K6-1 and 50B-3 cell lines, resistant to VP-16, a DNA topoisomerase II inhibitor, were established from two different types of cells respectively: human T-cell derived acute lymphoblastic leukemia cell line RPMI8402 and mouse mammary tumor cell line FM3A. IC50 values of K6-1 and 50B-3 cells to VP-16, evaluated by the colony forming ability on methyl cellulose medium, were 11- and 84-fold higher than their sensitive parental cell lines, respectively. Membrane permeability of the drug was not responsible for the resistance in K6-1 and 50B-3 cells. Quantitative analysis of drug-induced DNA cleavage (so called cleavable complex formation) was performed using 32P end-labeled pBR322 restriction fragments. The formation of the topoisomerase II-DNA cleavable complex stimulated by VP-16 in 50B-3 cells was approximately 1/5 compared with that of FM3A wild-type cells. Dot blot analysis of RNA extracted from these cell lines showed that the levels of mRNA for DNA topoisomerase II in 50B-3 cells were markedly decreased and that catalytic activity was reduced to 1/2-1/3 compared with that of parent cells. There was a slight reduction of DNA topoisomerase II mRNA in K6-1 cells. However, DNA topoisomerase II activities were similar in wild-type and K6-1 cells. In addition, 50B-3 cells showed cross resistance to VM-26, m-AMSA and adriamycin, whereas K6-1 cells exhibited increased resistance only to VM-26. These resistant cell lines did not show collateral sensitivity to CPT-11, a DNA topoisomerase I inhibitor. Southern blot analysis of genomic DNA did not show any change in the restriction pattern of the DNA topoisomerase II gene between the parental and their resistant lines. These findings suggest that the reduced levels in DNA topoisomerase II contribute to the drug resistance of 50B-3 cells.
 ...
PMID:DNA topoisomerase: the mechanism of resistance to DNA topoisomerase II inhibitor VP-16. 256 62


1 2 3 4 5 6 Next >>