Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Irinotecan hydrochloride (CPT-11), a DNA topoisomerase-I inhibitor, is now widely used in the treatment of various solid tumors, including colorectal, gastric, breast, lung, and ovarian cancer. Despite the good response shown in the late phase-II study, CPT-11 was not often employed in the treatment of malignant lymphoma, mainly because of severe leukopenia and diarrhea caused by the recommended schedule: 40 mg/m2 of CPT-11 on days 1 to 3, 8 to 10, 15 to 17, then discontinued for at least 2 weeks. In clinical use, administration of CPT-11 had to be ceased on days 15 to 17 in almost all cases, and on days 8 to 10 in a considerable number of patients. Subsequently, a lower dose schedule (less than 40 mg/m2) was developed. Our phase II trial employing a reduced dose of CPT-11 on days 1 and 2, plus ADM on day 3 with 3-week interval in patients with refractory and relapsed NHL showed a fairly good response of relapsed B-cell lymphoma and a substantial response of T-cell lymphoma with acceptable toxicity. The combination of a topoisomerase-I inhibitor (CPT-11) and a topoisomerase-II inhibitor is an interesting concept for the treatment of NHL. Another phase II trial in combination with CPT-11 and other anti-cancer drugs, particularly cisplatin or topoisomerase-II inhibitors, is warranted. A superior salvage chemotherapy regimen could be found in the future by investigating combinations of low-dose CPT-11 and cisplatin or topoisomerase-II inhibitors.
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PMID:Chemotherapy with irinotecan (CPT-11), a topoisomerase-I inhibitor, for refractory and relapsed non-Hodgkin's lymphoma. 1169 85

The therapeutic efficacy of irinotecan (CPT-11), a DNA topoisomerase inhibitor, is often limited by the induction of severe late-onset diarrhea. This prodrug and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), have a labile alpha-hydroxy-lactone ring that undergoes pH-dependent reversible hydrolysis. At physiological pH and higher, equilibrium favors the less toxic carboxylate form, whereas at acidic pH, the more potent lactone form is favored. We have reported previously that the initial uptake rate of CPT-11 and SN-38 by intestinal cells was significantly different between the respective lactone and carboxylate form. Results from the present study in HT-29 cells further demonstrate the correlation between the CPT-11/SN-38 initial uptake rate and the induced toxicity, cell cycle alteration, apoptosis, and colony-forming efficiency. The exposure of HT-29 cells to SN-38 for a limited period of time (<2 h) was sufficient to induce these events. Because the decreased initial uptake of SN-38 carboxylate resulted in a reduced cellular toxicity, we postulated that the CPT-11-induced diarrhea was preventable by influencing the equilibrium toward the carboxylate form and, thus, reducing its intestinal uptake. In the golden Syrian hamster model, p.o. sodium bicarbonate supplementation (5 mg/ml in drinking water) led to alkalization of the intestinal contents. In addition, this alkalization resulted in the reduction of the histopathological damage to the mucosa of the small and large intestine, as well as a 20% reduction of the intestinal SN-38 lactone concentration of animals receiving CPT-11 (20-50 mg/kg x 7 days). Taken together, these results from in vitro and in vivo studies support intestinal alkalization by sodium bicarbonate supplementation as a preventive mechanism against CPT-11-induced diarrhea. In addition, this provides a strong rationale for the usage of this measure as an adjunct to CPT-11 treatment.
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PMID:Intestinal alkalization as a possible preventive mechanism in irinotecan (CPT-11)-induced diarrhea. 1178 76

The precise mechanisms of resistance to camptothecin (CPT)-derived DNA topoisomerase (topo I) inhibitors and the determinants remain unclear. We found that a DNA repair protein, O(6)-methylguanine-DNA methyltransferase (MGMT), participated in resistance to irinotecan hydrochloride (CPT-11), its active metabolite SN-38, and a novel CPT derivative, DX-8951f. In 17 human cancer cell lines, MGMT gene expression level closely correlated with sensitivity to the CPT derivatives, and inhibition of MGMT activity by nontoxic 5 microM O(6)-benzylguanine augmented the drug activity in relation to the MGMT expression levels in 8 cell lines examined. Transfection of pCR / MGMT-sense into U-251MG and pCR / MGMT-antisense into T98G and HEC-46 cells revealed that increased MGMT expression decreased the sensitivity to CPT-11, SN-38, and DX-8951f, whereas repressed MGMT expression sensitized cells to the drugs. Western analysis revealed that treatment of MGMT-expressing T98G cells with the drugs caused a decrease of both MGMT and topo I in a dose-dependent manner. Although, in the transfectants, MGMT expression did not so closely correlate with the sensitivity to drugs as to nimustine hydrochloride (ACNU), MGMT is probably an important resistance determinant to CPT derivatives, and may play some role in the topo I-mediated DNA damage and / or the repair process.
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PMID:O(6)-methylguanine-DNA methyltransferase (MGMT) as a determinant of resistance to camptothecin derivatives. 1180 13

Numerous studies demonstrate that the chemopreventive effect of non-steroidal anti-inflammatory drugs on colon cancer is mediated through inhibition of cell growth and induction of apoptosis. For these effects non-steroidal anti-inflammatory drugs have been recently employed as sensitising agents in chemotherapy. We have shown previously that treatments with aspirin and NS-398, a cyclo-oxygenase-2 selective inhibitor, affect proliferation, differentiation and apoptosis of the human colon adenocarcinoma Caco-2 cells. In the present study, we have evaluated the effects of aspirin and NS-398 non-steroidal anti-inflammatory drugs on sensitivity of Caco-2 cells to irinotecan (CPT 11) and etoposide (Vp-16) topoisomerase poisons. We find that aspirin co-treatment is able to prevent anticancer drug-induced toxicity, whereas NS-398 co-treatment poorly affects anticancer drug-induced apoptosis. These effects correlate with the different ability of aspirin and NS-398 to interfere with cell cycle during anticancer drug co-treatment. Furthermore, aspirin treatment is associated with an increase in bcl-2 expression, which persists in the presence of the anticancer drugs. Our data indicate that aspirin, but not NS-398, determines a cell cycle arrest associated with death suppression. This provides a plausible mechanism for the inhibition of apoptosis and increase in survival observed in anticancer drug and aspirin co-treatment.
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PMID:Effect of non-steroidal anti-inflammatory drugs on colon carcinoma Caco-2 cell responsiveness to topoisomerase inhibitor drugs. 1198 87

The DNA topoisomerase inhibitor irinotecan (CPT-11, Camptosar) is being evaluated as a novel chemotherapeutic agent that may complement other agents and treatment modalities for small-cell lung cancer (SCLC). Combination chemotherapy is the most effective means of improving the survival of patients with extensive disease, but until recently, no combination demonstrated superior efficacy. In a recent Japanese phase III study, irinotecan in combination with cisplatin significantly improved the survival of previously untreated patients with extensive SCLC compared to standard etoposide/cisplatin therapy (median progression-free survival: 6.9 vs 4.8 months, P = .003; median overall survival: 12.8 vs 9.4 months, P = .002). Two additional phase III trials have been planned in the United States to confirm these results, and to investigate how the administration schedule of irinotecan/cisplatin may be modified to improve its therapeutic index. The results of phase I/II studies have shown that other irinotecan-based combinations demonstrate promising activity in this disease as both first- and second-line therapy. This article reviews the rationale for the use of irinotecan in SCLC, examines key findings from recent clinical studies of irinotecan-based therapy, and discusses how the use of irinotecan in combination with new noncytotoxic anticancer agents can and will be further explored.
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PMID:Irinotecan therapy for small-cell lung cancer. 1201 33

Apo2L/TRAIL exhibits enhanced apoptotic activity in tumor xenograft models when used in combination with the topoisomerase 1 inhibitor CPT-11. To investigate the cellular mechanisms involved in this increased tumor-killing activity, a series of in vitro experiments were conducted using the human colon carcinoma cell line (HCT116). Apo2L/TRAIL induced a transient upregulation of DR5 mRNA, while CPT-11 increased both death and decoy receptor expression. Upregulation of decoy receptors by CPT-11 was partially inhibited by co-administration of Apo2L/TRAIL. CPT-11 treatment resulted in accumulation of cells at G(2)M-phase and correlated with a substantial increase in the protein levels of the cyclin-dependent kinase inhibitor p21. However, cells co-treated with CPT-11 and Apo2L/TRAIL, or pretreated with CPT-11 for up to 24 h followed by 2 h Apo2L/TRAIL, resulted in a caspase-dependent degradation of p21, reversal of G(2)-M phase arrest with a concomitant increase in apoptosis. The sequential treatment produced the greatest induction of DR5 and DR4, caspase-3-like cleavage/activation and p21 degradation, as well as increased apoptosis. These data indicate that the up-regulation of Apo2L/TRAIL ligand and its death receptors as well as cleavage of p21 protein in the Apo2L/TRAIL plus CPT-11 treatment contributes to the positive cooperation between these agents in enhancing tumor cell apoptosis.
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PMID:Enhanced tumor killing by Apo2L/TRAIL and CPT-11 co-treatment is associated with p21 cleavage and differential regulation of Apo2L/TRAIL ligand and its receptors. 1203 63

The DNA topoisomerase inhibitor irinotecan (CPT-11, Camptosar) is being evaluated as a novel chemotherapeutic agent for small-cell lung cancer that may complement other agents and treatment modalities. Combination chemotherapy is recognized as the most effective means of improving survival in patients with extensive-stage small-cell lung cancer, but until recently, no one combination had emerged as superior. In a recent Japanese phase III study, irinotecan in combination with cisplatin significantly improved survival of previously untreated patients with extensive small-cell lung cancer compared with standard etoposide/cisplatin therapy (median progression-free survival: 6.9 vs 4.8 months, P < .001; median overall survival: 12.8 vs 9.4 months, P = .0021). Two additional phase III trials are planned to confirm these results in the United States, and to investigate how the irinotecan/cisplatin administration schedule may be modified to improve therapeutic index. This article will review the use of irinotecan in combination with cisplatin in patients with small-cell lung cancer.
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PMID:Irinotecan plus cisplatin in small-cell lung cancer. 1237

Many women diagnosed with invasive breast cancer have undetected occult metastases at the time of their primary tumour diagnosis. The development and growth of these micro-metastases relies heavily on angiogenesis. Therefore, administering an angiogenesis-blocking treatment from the time of diagnosis could reduce the incidence of metastasis and, ultimately, increase patient survival. It is hypothesized that an antiangiogenesis strategy combining fever-range whole-body hyperthermia (FR-WBH) and metronomic chemotherapy could inhibit the development of metastatic disease with minimal toxicity. To test this theory, a low, daily dose of the topoisomerase-I inhibitor irinotecan hydrochloride (CPT-11) was administered over a prolonged period of time to rats bearing the highly metastatic MTLn3 mammary adenocarcinoma primary tumour surgically excised on day 12 after implantation. The metronomic CPT-11 was combined with long-duration, low-temperature, fever-range whole body hyperthermia (FR-WBH). This systemic hyperthermia enhances chemotherapy-induced cytotoxicity as well as immunological activity. Both the group treated with FR-WBH alone and the combined FR-WBH + CPT-11 group had delayed onset and reduced incidence of axillary lymph node metastases compared to control (p < 0.05). Combination therapy of FR-WBH + CPT-11 resulted in a significantly greater inhibition of axillary lymph node metastasis volume compared to both control and CPT-11 alone (p < 0.02) at day 16. Interestingly, none of the therapies significantly affected inguinal lymph node metastases. Lung metastases were decreased by 36% at the time of death in rats treated with FR-WBH + CPT-11, by 25% in the CPT-11 alone group and by 14% in the FR-WBH alone group. Rats treated with FR-WBH, + CPT-11 survived significantly longer (35%) than control animals (p < 0.04). Neither significant body weight loss nor gastrointestinal toxicity was observed in any group. These data suggest that, after excision of the primary tumour, FR-WBH and metronomic CPT-11 can be safely combined to reduce distant lymph node and lung metastases and, thus, to increase survival.
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PMID:The effect of whole-body hyperthermia combined with 'metronomic' chemotherapy on rat mammary adenocarcinoma metastases. 1262 34

The topoisomerase-I inhibitor irinotecan (CPT-11) is currently used in Phase I/II trials for the treatment of patients with recurrent malignant gliomas. Protein kinase C (PKC) inhibitors such as high-dose tamoxifen and hypericin also have been used in the treatment of malignant gliomas. The current study examined the role of PKC inhibitors as chemosensitizers for CPT-11 and their proposed mechanism of action. Two glioma cell lines (A-172 and U-87) and one primary glioma cell culture (LA-567) were used. Proliferation ((3)H-thymidine) and cytotoxicity (methylthiotetrazole) studies were performed using CPT-11 (0-100 microM) alone, 7-ethyl-10-hydroxy camptothecin (SN-38) (0-1000 nM) alone or in the presence of a PKC inhibitor, tamoxifen (10 microM), hypericin (10 microM), calphositin C (400 nM), or staurosporine (10 nM). The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL) assay was used to determine apoptosis as the mechanism of cytotoxicity; alterations in bcl-2 and bax expression were determined using Western blot analysis. Conversion of CPT-11 to SN-38 by glioma cells was determined using high-performance liquid chromatography (HPLC) analysis. Increasing CPT-11 and SN-38 concentrations induced cytotoxic morphologic changes, decreased proliferation, and increased cytotoxicity on all glioma cell lines tested. These changes were increased in the presence of a PKC inhibitor. The mechanism of the cytotoxicity was determined to be apoptosis by the TUNEL assay. The combination of a PKC inhibitor with CPT-11 or SN-38 led to decreased expression of the antiapoptotic protein bcl-2, and increased expression of the proapoptotic protein bax. HPLC analysis demonstrated conversion of CPT-11 to SN-38 by glioma cells. A combination of CPT-11 or SN-38 with a PKC inhibitor was found to lead to a decrease in proliferation and an increase in apoptosis in malignant glioma cells. The induction of apoptosis was secondary to a decrease in bcl-2 and an increase in bax expression. Glioma cells are capable of converting CPT-11 to SN-38 by intrinsic tumor carboxylesterases.
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PMID:Combination therapy with irinotecan and protein kinase C inhibitors in malignant glioma. 1271 58

Radiation therapy has traditionally been the treatment of choice for locally or regionally advanced cancer, but its therapeutic efficacy is often hindered by limited tolerance of normal tissues and by tumor radioresistance. To improve therapeutic outcome, radiotherapy is frequently combined with chemotherapeutic drugs that are themselves cytotoxic and may sensitize cells to radiation. Solid evidence exists that administering standard chemotherapeutic agents during the course of radiotherapy (concurrent chemoradiotherapy) increases both local tumor control and patient survival in a number of cancer sites. These therapeutic improvements, however, have been achieved at the expense of considerable normal tissue toxicity. To improve chemoradiotherapy further, there have been extensive explorations of the potential of newer chemotherapeutic agents, including irinotecan (CPT-11, Camptosar) and other topoisomerase inhibitors. Preclinical studies have shown that these agents are potent radiosensitizers, providing a strong biologic rationale for using these drugs in combination with radiotherapy. These studies also generated information critical for designing effective treatment schedules in clinical settings. The therapeutic efficacy of topoisomerase inhibitor-radiation combinations is currently being tested clinically. Recent advances in molecular biology have discovered many cellular molecules, including the cyclooxygenase-2 (COX-2) enzyme, that promote tumor cell survival and are responsible for tumor resistance to cytotoxic agents, and hence may serve as potential targets for augmentation of radio (or chemo) response. COX-2 is often overexpressed in premalignant lesions and cancer, and is involved in carcinogenesis, tumor growth, and metastatic spread. Preclinical studies provided solid evidence that inhibition of this enzyme with selective COX-2 inhibitors prevents carcinogenesis, slows the growth of established tumors, and enhances tumor response to radiation without appreciably affecting normal tissue radioresponse. The mechanisms of enhancement of tumor radioresponse involve direct actions on tumor cells and indirect actions, primarily on tumor vasculature. COX-2 inhibitors also improve tumor response to chemotherapeutic agents, including irinotecan. Additional therapeutic benefit was observed for celecoxib (Celebrex), a selective COX-2 inhibitor, consisting of a strong reduction in irinotecan-induced diarrhea. Thus, selective targeting of COX-2 may potentially improve radiotherapy, chemotherapy, or chemoradiotherapy--a therapeutic strategy that is currently being tested in clinical trials.
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PMID:Improvement of radiotherapy or chemoradiotherapy by targeting COX-2 enzyme. 1280 Jun 1


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