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 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.
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PMID:[DNA topoisomerase inhibitor]. 133 23

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

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.
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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.
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PMID:Mechanism of cross-resistance to a camptothecin analogue (CPT-11) in a human ovarian cancer cell line selected by cisplatin. 134 10

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.
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PMID:Collateral drug sensitivity induced in CPT-11 (a novel derivative of camptothecin)-resistant cell lines. 216 67

A new water-soluble derivative of camptothecin, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), did not exhibit potent antitumor activity in vitro against experimental tumor cells. The 50% effective doses of CPT-11 against KB and L1210 cells were 1100 and 5500 ng/ml, respectively. These values were markedly higher than those of camptothecin (CPT, 0.98 and 3.7 ng/ml) or 7-ethyl-10-hydroxycamptothecin (SN-38, 0.37 and 3.6 ng/ml). CPT-11 was found to be converted into SN-38 in mouse serum. In vitro incubation of CPT-11 in mouse serum or tissue homogenate enhanced the growth-inhibitory activity much more than that expected from the concentration of CPT-11. This enhancement of the activity coincided with that expected from the SN-38 concentration in incubated serum or homogenate, though the contribution of CPT-11 could not be refuted. SN-38 is considered to play a major role in the antitumor activity when CPT-11 is incubated in serum or homogenate. The plasma CPT-11 concentration decreased biexponentially after i.v. administration of CPT-11 into mice with a biological half-life of 0.8 to 1.1 h. The area under the plasma CPT-11 concentration-time curve showed dose dependency. The SN-38 concentration decreased for the first 30 min after administration and was then maintained for a few hours at about 0.1 microgram/ml after i.v. administration of 20 and 40 mg/kg of CPT-11 followed by the log-linear terminal phase with a half-life of about 2 h which was independent of the dose. It is suggested that the maintenance of plasma SN-38 concentration might be necessary for it to exhibit antitumor activity in vivo.
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PMID:Metabolism and pharmacokinetics of the camptothecin analogue CPT-11 in the mouse. 230 25

Camptothecins belong to a group of anticancer agents with a specific mechanism of action: stabilization and trapping of eukaryotic DNA topoisomerase I (top1) cleavable complexes. Two water-soluble camptothecin derivatives are in clinical trial, and their anticancer activity appears promising: topotecan and CPT-11. The latter is hydrolyzed to its active metabolite, SN-38. We have previously reported that SN-38 is among the most cytotoxic camptothecin derivatives and that the cleavable complexes induced by SN-38 are more stable than those induced by CPT in human colon carcinoma cells [Tanizawa et al. (1994) J. Natl. Cancer Inst, 86, 836-842]. Top1 inhibition was further investigated by determining the salt-induced religation rates of top1-cleavable complexes in fragments from the top1 cDNA. Religation depended on both the local DNA base sequence and the drug structure. Cleavable complexes induced by SN-38 and 10,11-methylenedioxycamptothecin were markedly more stable (less rapidly reversible) than those induced by CPT, topotecan, and 9-aminocamptothecin. The stability of 10-hydroxycamptothecin-induced cleavable complexes was intermediate to those of CPT and SN-38, indicating that both the 10-hydroxy and the 7-ethyl group of SN-38 probably interact with the drug binding site of top1-cleavable complexes. A DNA oligonucleotide containing a single top1 cleavage site was also used to compare the camptothecin derivatives. The salt stability of drug-induced cleavable complexes in the top1 oligonucleotide was correlated with the drug potencies to induce top1 cleavage. Cell killing requires that trapped cleavable complexes be converted to DNA damage as a result of replication fork collision.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential stabilization of eukaryotic DNA topoisomerase I cleavable complexes by camptothecin derivatives. 776 31

The kinetics of the in vivo interconversion of the carboxylate and lactone forms of the prodrug irinotecan, 7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin (CPT-11), and its active metabolite SN-38 were studied in five patients using a HPLC method that allows the simultaneous determination of all four compounds and detects any hydrolysis of lactones due to inadequate sample handling and storage. The apparent conversion of CPT-11 lactone to the carboxylate in vivo was rapid with a mean half-life of 9.5 min; the carboxylate became the predominant form of plasma CPT-11 soon after the end of the infusion. The ratio of the area under the plasma concentration-time curves of the lactone to total CPT-11 was 36.8 +/- 3.5% (SD). In contrast, SN-38 was present predominantly as the lactone at all times and with little interpatient variability (lactone/total area under the plasma concentration-time curve ratio, 64.0 +/- 3.4%). This may explain in part the promising activity of CPT-11 because CPT derivatives are active against their target, topoisomerase I, only in their lactone form.
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PMID:Kinetics of the in vivo interconversion of the carboxylate and lactone forms of irinotecan (CPT-11) and of its metabolite SN-38 in patients. 798 23

A camptothecin analog, ((4s)-4,11-diethyl-4-hydroxy-9-[(4- piperidinopiperidino)carbonyloxy]dione hydrochloride trihydrate), (CPT-11), is a recently developed topoisomerase I (Topo I) inhibitor which attracts the attention of clinicians because of its high antitumor activity. We established a CPT-11-resistant human ovarian cell line, HAC2/CPT, from the parental HAC2 cell line. An in vitro drug sensitivity assay revealed that HAC2/CPT was 9.7 and 4.7 times as resistant as HAC2 to CPT-11 and 7-ethyl-10-hydroxy-CPT-11 (SN-38), an active metabolite of CPT-11, respectively. HAC2/CPT showed no cross-resistance to other drugs tested (adriamycin, etoposide, cisplatin and Taxol), suggesting that HAC2/CPT acquired a phenotype specifically resistant to the Topo I inhibitor. In order to elucidate the mechanism of the resistance, we measured Topo I activity of HAC2 and HAC2/CPT. The activity of Topo I of HAC2/CPT was reduced to half of that of the parental HAC2 cells. To determine the cause of the decreased activity of Topo I, the mutation of the Topo I gene was searched for by the polymerase chain reaction and the reverse transcriptase analysis. Topo I gene mutation was not detected. The amount of Topo I protein was measured by immunoblotting and a marked decrease of Topo I protein was observed in HAC2/CPT. These results suggest that the decreased protein content of Topo I causes the decreased activity of Topo I and the decreased sensitivity of HAC2/CPT to Topo I inhibitors.
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PMID:Establishment of a CPT-11-resistant human ovarian cancer cell line. 807 81

Suramin, a highly sulfonated drug, has been reported to be effective against several human malignancies in vitro and in vivo, and currently is undergoing clinical trials against prostate tumors. The biochemical and molecular mechanisms for suramin's antiproliferative activity are not clear. In order to define the biochemical basis for its antitumor activity and to enhance suramin's chemotherapeutic potential while decreasing its toxicity, we have examined interactions of suramin with topoisomerase I and II and several clinically active anticancer drugs against the human prostate (PC3 and LNCaP) cancer cell line. While etoposide, m-AMSA, camptothecin, and SN-38 (the active metabolite of CPT-11) were active in killing prostate cells as single agents, combinations of suramin and these agents were antagonistic against these cells. We found that suramin inhibited activities of purified topoisomerase I and II in vitro as measured by relaxation and cleavage assays. Further studies indicated that suramin also inhibited the drug-induced DNA damage in vitro and in isolated nuclei. These findings indicate that combinations of suramin with topoisomerase inhibitors, for example, VP-16, m-AMSA, or CPT, may not be beneficial to patients receiving suramin-containing chemotherapy.
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PMID:Suramin inhibits DNA damage in human prostate cancer cells treated with topoisomerase inhibitors in vitro. 839 91


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