Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The anticancer agent saintopin induces DNA cleavage mediated by both topoisomerase (topo) I and topo II in vitro through stabilization of the reversible enzyme-DNA cleavable complex. We established saintopin-resistant cell lines (KB/STP-1 and KB/STP-2) from human epidermoid cancer KB cells by stepwise exposure to increasing doses of the drug. KB/STP-1 and KB/STP-2 cells showed 12- and 44-fold increases, respectively, in resistance to saintopin relative to that of KB cells. Both saintopin-resistant cell lines showed only small reductions in sensitivity to the topo II inhibitor etoposide but developed marked cross-resistance to the topo I-targeting camptothecin derivative CPT-11 [(4s)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbony loxy] dione hydrochloride trihydrate] and its active form, SN-38 (7-ethyl-10-hydroxycamptothecin). In contrast, both KB/STP-1 and KB/STP-2 cells showed increased collateral sensitivity to cisplatin, a nitrosourea derivative, mitomycin C, and UV light. The protein concentration, activity, and mRNA abundance of both topo I and topo II were similar in KB/STP-1, KB/STP-2, and the parental KB cells. There were no significant changes in the drug-stabilized topo-DNA cleavable complex formation in KB and KB/STP-2 cells. Two point mutations were detected in topo I cDNA from KB/STP-2 cells, but these were also present in KB cells. Topo I mRNA abundance decreased markedly immediately after exposure of KB/STP-2 cells to saintopin; no such effects were apparent in KB cells. In contrast, topo II mRNA was not markedly affected by saintopin in either KB or KB/STP-2 cells. Treatment with CPT-11 or SN-38 also induced a markedly greater and more persistent reduction in topo I mRNA abundance in KB/STP-2 cells than in KB cells. Etoposide had no marked effect on topo I mRNA abundance in either KB/STP-2 or KB cells. Topo I mRNA was highly unstable in KB/STP-2 cells in comparison to KB cells when incubated with saintopin. This novel regulation of topo I mRNA by topo I-targeting agents could be associated with acquirement of drug resistance to saintopin or SN-38/CPT-11 in KB/STP-2 cells.
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PMID:Drug-induced down-regulation of topoisomerase I in human epidermoid cancer cells resistant to saintopin and camptothecins. 862 10

Two new drugs from two new chemotherapy compound families were developed concomitantly: Taxoter (docetaxel), a taxane derivate and CPT 11 (irinotecan) a topoisomerase inhibitor. Six phase I trials of Taxoter were performed. The limiting toxicity is neutropenia. The recommended dosage for phase II trial is 100 mg/m2 administered in 1 hour perfusion, every 21 days. Neutropenic fever is unfrequent. Other toxicities are mucositis, skin toxicity, hypersensibility reaction, weight gain and oedema. None of these toxicities were limiting. Six phase I studies were conducted to determine the maximum tolerated dose of CPT 11 (irinotecan). Two different schedules were studied: the weekly 30-90 minutes infusion and an infusion administered every three weeks in one day or daily over three or five consecutive days. The limiting toxicity of the weekly schedule is diarrhea. Therefore the recommended dosage is 100-150 mg/m2/week. While dose limiting toxicities in the three week schedule are diarrhea as well as neutropenia. The recommended dose is 350 mg/m2. Since diarrhea appeared to be the major problem in achieving high dose intensity with CPT 11, a dose escalation trial with drug support against diarrhea was performed. A recommended dosage of 500 mg/m2 is therefore described. These two drugs are under evaluation in a large spectrum of tumors. Their original mechanism of action suggests interesting therapeutic properties. Clinical studies in combination with other drugs are in progress to define the role of topoisomerase I inhibitors and taxane in cancer therapy.
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PMID:[Taxotere (docetaxel) and CPT 11 (irinotecan): phase I trials]. 867 54

We examined the effects of the introduction of H-ras oncogene into murine cell line NIH3T3 on growth inhibition by topoisomerase-I (topo-I) inhibitors. The H-ras-transformed cells (pT22-3) showed approximately 12-fold increased sensitivity to a novel topo-I inhibitor, NB-506 [6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosyl) -5H-indolo(2,3-a)pyrrolo(3,4-c) carbazole-5,7(6H)-dione], compared with the parental NIH3T3 cells. pT22-3 also showed increased sensitivity to other topo-I inhibitors such as camptothecin (approx. 3.0-fold) and CPT-11 (irinotecan, approx. 3.0-fold). Transformation of NIH3T3 by another oncogene (erbB2) did not affect their sensitivity to these topo-I inhibitors. pT22-3 had approximately 32-fold higher topo-I activity than NIH3T3, but the same topo-I content. In a cell-free system, topo-I activity was increased 2-fold by addition of the H-ras protein precipitated from pT22-3 cells. Topo I in the nuclear extract of pT22-3 was eluted easily by low concentrations of NaCl compared with that of NIH3T3, suggesting a qualitative change in pT22-3 topo 1. Increased phosphorylation of topo I was observed in pT22-3. Furthermore, NB-506 decreased the amount of the GTP-bound form of the H-ras product in pT22-3 cells. These results suggest that the high growth-inhibitory effect of a topo-I inhibitor, NB-506, on H-ras-transformed NIH3T3 cells is due to the H-ras-mediated signal-transduction pathway.
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PMID:Hypersensitivity of NIH3T3 cells transformed by H-ras gene to DNA-topoisomerase-I inhibitors. 878 62

A mouse mammary carcinoma FM3A cell line resistant to the DNA topoisomerase (topo) II-targeting agent, etoposide (VP-16), FM3A/VP-2B, had a markedly reduced growth rate at a low temperature (33 degrees C). The cells had the following properties: (a) FM3A/VP-2B, which had 24-fold higher resistance to VP-16 than its parental line, FM3A, was cross-resistant to doxorubicin, but not to a camptothecin derivative, CPT-11. (b) Cold-resistant revertants from FM3A/VP-2B, R-6 and R-11, remained 8- to 9-fold more resistant to VP-16 and 2- to 3-fold more resistant to doxorubicin. (c) FM3A/VP-2B had one-fourth the level of topo II activity and one-third of the topo II alpha content and mRNA of FM3A. R-6 and R-11, however, had levels similar to FM3A. (d) FM3A/VP-2B and FM3A had a 3-base deletion at position 4170 on one allele on the topo II alpha cDNA, but expression of the wild-type and the deletion allele was not appreciably changed in both cell lines. Decreased topo II alpha expression might have led to the acquisition of drug resistance to etoposide in FM3A/VP-2B, and appeared to be linked with the cold-sensitive growth. We also present a corrected mouse topo II alpha cDNA sequence.
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PMID:Decreased DNA topoisomerase II alpha expression and cold-sensitive growth in a mouse mammary cancer cell line resistant to etoposide and doxorubicin. 888 12

Irinotecan (CPT-11) has been reported to be cytotoxic to tumor cells through its inhibitory activity on type I DNA topoisomerase. CPT-11 has also been shown to have several unique biological activities apart from direct cytotoxicity. We investigated the ability of CPT-11 to induce tumor necrosis factor (TNF) production. Human peripheral blood mononuclear cells (MNCs) were incubated with LPS, CPT-11, or with vinblastin sulfate as a control. The priming effect of CPT-11 on endogenous production of TNF was examined by injecting the drug intravenously into mice, followed 3 hours by the injection of OK432. At a dose of 200-400 micrograms/kg, CPT-11 showed a significant priming effect. A significant amount of TNF was released when MNCs were incubated with 100-300 microM of CPT-11 for more than 4 hours, but not with vinblastin sulfate, indicating a triggering effect of TNF production on MNCs in vitro. These effects may be advantageous in cancer therapy.
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PMID:Induction of tumor necrosis factor by a camptothecin derivative, irinotecan, in mice and human mononuclear cells. 891 43

CPT-11, a new semisynthetic derivative of camptothecin, is active in a number of tumor types in the clinic, including colon cancer. CPT-11 is a drug that is converted into the active metabolite SN-38 by a carboxylesterase. Experiments were performed to obtain more insight in the cellular characteristics in 5 unselected human colon-cancer cell lines that account for the differential sensitivity to CPT-11 and SN-38. In vitro, the sensitivity to CPT-11 and SN-38 was highest in LS174T and COLO 320 cells, intermediate in SW1398 cells and lowest in COLO 205 and WiDr cells. SN-38 was 130 to 570 times more active than CPT-11. CPT-11 induced complete remissions in 6 out of 12 COLO 320 tumors grown as subcutaneous xenografts, but was not effective in WiDr tumors. The cellular carboxylesterase activity did not relate to the sensitivity to CPT-11. The enzyme activity was higher in normal mouse tissues, i.e., serum and liver, than in COLO 320 or WiDr xenografts, indicating that tumor carboxylesterase is of minor importance for CPT-11 efficacy. The topoisomerase-1 mRNA expression in tumor cells was not predictive of the antiproliferative effects of CPT-11 or SN-38. We observed a positive relationship between the DNA topoisomerase-1 activity and the cellular sensitivity to carboxylesterase-activated CPT-11 (r = 0.75, p < 0.1) as well as to SN-38 (r = 0.89, p < 0.05). The higher topoisomerase-1 activity in COLO 320 cells and tumors when compared with that in WiDr cells and tumors reflected the differences in sensitivity to the drug(s). In conclusion, the DNA topoisomerase-1 activity was the best determinant for CPT-11/SN-38 sensitivity in this panel of unselected human colon-cancer cell lines.
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PMID:CPT-11 in human colon-cancer cell lines and xenografts: characterization of cellular sensitivity determinants. 903 37

This study was designed to elucidate the mechanisms of cisplatin (CDDP) resistance using two human ovarian cancer cell lines, KF and TYK, and two CDDP-resistant lines, KFr and TYK/R, derived from the former lines. KFr and TYK/R showed about 3-fold higher resistance to the cytotoxic effects of CDDP than their parental lines. They also showed a significant increase in sensitivity to not only etoposide, but also (+)-(4S)-4, 11-diethyl-4-hydroxy-9-[(4-piperidino -piperidino)carbonyloxy]-1H -pyrano[3',4':6,7]inodolizino[1,2-b]quinoline-3,14(4H, 12H)-dione hydrochloride trihydrate (CPT-11). Cellular CDDP accumulation levels in KFr and TYK/R were decreased from those of the parental cells. By contrast, the cellular glutathione (GSH) content in KFr cells was 1.7-fold higher than that in KF, whereas TYK/R cells had a 40% lower content than TYK cells. Cellular mRNA levels of drug-resistance-related genes, such as DNA topoisomerase (topo) I and topo II, glutathione S-transferase-pi (GST-pi), gamma-glutamylcysteine synthetase (gamma-GCS), and metallothionein (hMT) genes, were compared between drug-sensitive KF or TYK and KFr or TYK/R. KFr cells had 8.5- and 24.7-fold higher mRNA levels of gamma-GCS and topo II genes than KF cells while KFr had only a slight increase in GST-pi mRNA level as compared with KF. By contrast, TYK/R cells had 2.9- and 1.7-fold higher hMT and topo I mRNA levels than TYK cells. Acquisition of CDDP resistance in human ovarian cancer cells thus appeared to be related mainly to expression of gamma-GCS, topo II and hMT genes, and partly to that of topo I and GST-pi genes, in addition to a decrease in CDDP accumulation.
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PMID:Altered expression of gamma-glutamylcysteine synthetase, metallothionein and topoisomerase I or II during acquisition of drug resistance to cisplatin in human ovarian cancer cells. 911 51

Irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin, (CPT-11) resistance was overcome by using a biscoclaurine alkaloid, cepharanthine, in CPT-11- and multidrug-resistant 50MT-1 cells. 50MT-1 cells were established from a mouse breast-cancer cell line, FM3A, by subjecting the cells to a low dose of CPT-11 continuously. 50MT-1 cells exhibited resistance to CPT-11 (40-fold in colony-formation assay) and to other drugs such as doxorubicin (11.7-fold) and etoposide (VP-16) (16.8-fold). The plasma trans-membrane potential was lower in 50MT-1 cells than in FM3A cells, although there were no differences in expressions of P-glycoprotein and of DNA topoisomerase-I and -II proteins. The lower membrane potential in 50MT-1 cells was augmented by co-treatment with a non-toxic dose of cepharanthine. CPT-11 resistance in 50MT-1 cells was overcome (5.0- to 1.4-fold, 6-hr exposure) by the co-treatment with cepharanthine through increasing intracellular accumulation of CPT-11. Resistance to doxorubicin and VP-16 was also overcome by cepharanthine treatment (2.5- to 0.69-fold and 4.2- to 1.4-fold respectively). We conclude that the modification of plasma trans-membrane potential by cepharanthine should be effective in overcoming CPT-11 and multidrug resistance in 50MT-1 cells.
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PMID:Overcoming CPT-11 resistance by using a biscoclaurine alkaloid, cepharanthine, to modulate plasma trans-membrane potential. 921 36

The anti-tumor activity of irinotecan (CPT-11), a DNA-topoisomerase 1 inhibitor, was evaluated in 5 advanced stage subcutaneous medulloblastoma xenografts in nude mice, using different schedules of administration. With a 5-day schedule, the highest i.v. dose tested (40 mg kg-1 day-1) induced complete regressions in all xenografts but 1, and delays in tumor growth always exceeded 30 days. Two xenografts, IGRM11 and IGRM33, were highly sensitive, and animals survived tumor-free beyond 120 days after treatment. CPT-11 clearly retained its anti-tumor activity at a lower dosage (27 mg kg-1 day-1). CPT-11 was significantly more active than cyclophosphamide, thiotepa and etoposide against the 3 xenografts evaluated. To study the schedule dependency of its anti-tumor activity, CPT-11 was given i.v. at the same total doses over the same period (33 days) using either a protracted or a sequential schedule in IGRM34-bearing mice. With a dose of 10 mg kg-1 day-1 given on days 0-4, days 7-11, days 21-25 and days 28-32 (total dose, 200 mg kg-1), 3 of 6 animals were tumor free on day 378. The same total dose given with a sequential schedule, i.e., 20 mg kg-1 day-1 on days 0-4 and days 28-32, failed to induce complete regression. The plasma pharmacokinetics of CPT-11 and SN-38 were studied in IGRM34-bearing animals after a single i.v. dose of 10 and 40 mg kg-1. The plasma clearance rate of CPT-11 was dose dependent. The ratio between the SN-38 and CPT-11 area under the curve in plasma was 0.4-0.65, i.e., significantly higher than that observed in humans at the maximum tolerated dose (0.01-0.05). Conversely, this ratio was 10-fold lower in tumor than in plasma. Clinical development of irinotecan is warranted in pediatric malignancies.
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PMID:Potent therapeutic activity of irinotecan (CPT-11) and its schedule dependency in medulloblastoma xenografts in nude mice. 933 24

Five promising new drugs for gynecological cancer were reviewed. Taxans (Paclitaxel: Taxol and Docetaxel: Taxotere) diterpenoid plant products enhance the polymerization of tublin. Taxol showed significant activity for platinum refractory ovarian cancer in a phase 1 clinical trial in the United States. The combination with cisplatin (CDDP) showed superior results to CDDP plus Cyclophosphamide and has been recognized as a new standard in adjuvant chemotherapy for advanced ovarian cancer. The major toxicities are myelosuppression, alopecia, and hypersensitivity reactions (HSRs). HSRs were overcome by pretreatment with anti-histamines and over 24 hours administration. It was also reported that Taxol was administered safely by over 3 hours infusion with reduced myelotoxicity, but the incidence of HSRs may be increased. Clinical trials of intraperitoneal administration and combination with Carboplatin (CBDCA) are ongoing. Taxotere, an analog of Taxol, is also effective as Taxol with a low incidence of HSRs. Topoisomerase inhibitors (Irinotecan hydrochloride: CPT-11 and Topotecan) have promising antitumor activity for ovarian and cervical cancer. CPT-11 is a semisynthetic camptothesin analog developed in Japan. It was also effective for platinum-resistant ovarian cancer, such as mucinous and clear cell carcinoma. An adverse effect was observed in the combination of CPT-11 and CDDP. The phase 1 clinical trial showed a 40% response rate against recurrent ovarian cancer. CPT-11 50-60 mg/m2 (day 1,8,15) and CDDP 50-60 mg/m2 (day 1) are a recommended schedule. The major toxicities are neutropenia and diarrhea. Thrombocytopenia is not severe and diarrhea is also controllable. Topotecan is also a promising topoisomerase inhibitor and reported superior result to Taxol for platinum refractory ovarian cancer. A phase II trial is ongoing for ovarian and cervical cancer in Japan. Nedaplatin, a new analog of cisplatin, has similar activity especially for cervical cancer with less myelotoxicity and nephrotoxicity.
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PMID:[Promising new drugs for gynecological cancer]. 935 Feb 38


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