Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The establishment of reliable preclinical test is essential for the reasonable clinical trial. As a methodology for the screening of new active anticancer agents, disease oriented strategy using human tumor cell lines has been proposed in USA. The important questions in DOS are to determine the representative cell lines of specific cancer and it is also extremely important to decide the numbers of cell lines used for the screening. CPT-11, topoisomerase I inhibitor, developed in my country has been demonstrated to be active against lung cancer cell lines compared with mice tumors such as S-180 and P-388. However, no compound is demonstrated to be clinically active so far by this methodology. The criteria for the application of clinical trial are obscure and each drug company decides empirically by themselves. We have proposed to use PEI (predictive efficacy index) for the prediction of antitumor activity of new compounds. The clinical effect of new platinum analogue well correlated with this value. We have conducted phase II trial of 5-FU + LV against NSCLC without no prior chemotherapy. No responder was observed in the trial. Augmentive effect of leucovorin on the cytotoxicity of 5-FU and FdUrd was examined in vitro against NSCLC and colon cancer cell lines. Leucovorin stimulated the cytotoxicity of both drugs only against colon cancer cell lines. We tried to predict the response rate of new platinum derivative based on the data of bioassay of patient's serum administrated with platinum compounds. The predicted response rates of 254-S were 57-67% and 16-27% against SCLC and NSCLC, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Preclinical trials from the standpoint of clinical trials]. 185 17

A total of three topoisomerase I inhibitors, including topotecan, CPT-11 (irinotecan), and intoplicine, have been studied in both preclinical and clinical/clinical pharmacology studies. In in vitro testing against human tumor colony-forming units, all three compounds were significantly more effective when tested as a continuous exposure as compared with a 1-h exposure. The dose-limiting toxicities were different for all three of the agents, with neutropenia and thrombocytopenia being dose-limiting for topotecan; diarrhea, for CPT-11; and hepatotoxicity, for intoplicine. In these phase I studies a number of marginal responses were noted with topotecan; partial and marginal responses, with CPT-11 (particularly in patients with colon cancer); and no response, with intoplicine. The detailed pharmacology of all three agents documented a very short half-life for topotecan, an intermediate half-life for CPT-11, and a prolonged half-life for intoplicine. Based on our experience to date, these compounds (particularly CPT-11) have promise as useful additions to our tremendous therapeutic armamentarium.
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PMID:Preclinical and phase I trials of topoisomerase I inhibitors. 807 26

Irinotecan hydrochloride (CPT-11), topotecan, sobuzoxane, NC-190, and IST-622 are unique topoisomerase inhibitors and are investigational in Japan. CPT-11 is a water-soluble, semisynthetic derivative of camtothecin. CPT-11 shows its anticancer activity by inhibiting topoisomerase I activity, now a target of anticancer agents with major interest. Recent clinical trials reveal that CPT-11 is very effective in the treatment of cancer including lung cancer, cervical cancer, ovary cancer, stomach cancer, colon cancer, and non-Hodgkin's lymphoma. Major dose limiting toxicities are leukopenia and diarrhea, and are dose related. Topotecan is an another semisynthetic derivative of camtothecin and is also topoisomerase I inhibitor. Topotecan has undergone phase I clinical evaluations in USA, europe, and recently in Japan. DLF are leukopenia and neutropenia. Topotecan is more hydrophilic than its parent compound and shows lesser protein binding. Renal excretion appears to be the major route of elimination. Sobuzoxane (MST-16) is a unique derivative of dioxopiperazine, an inhibitor of topoisomerase II. In phase II studies, definite anticancer effects are observed in patients with non-Hodgkin's lymphoma and adult T-cell leukemia/lymphoma. Responses are seen even in pretreated cases. Leukopenia is also dose-limiting. Non-hematologic toxicities are mild and include alopecia and G.I. toxicities. NC-190 is a novel benzophenazine derivative with excellent antitumor activities against murine tumors. NC-190 also inhibits topoisomerase II. Now the drug is an early clinical phase II studies in Japan. Toxicities include bone marrow suppression, transient mild to moderate liver enzyme elevation, alopecia and mild G.I. toxicities. Tumor responses are occasionally encountered. IST-622 is a semisynthetic derivative of chartreusin. The drug is an inhibitor of topoisomerase II (and I in high concentration). IST-622 shows excellent, broad anticancer activity against murine tumors. The drug is well absorbed from small intestine. IST-622 is now in phase I clinical trial in Japan.
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PMID:[Topoisomerase inhibitors developing in Japan]. 842 86

We examined whether heat stress could enhance the sensitivity of human colon cancer WiDr cells to topoisomerase II-targeting anticancer agents, etoposide (VP-16) and teniposide (VM-26), and also determined the most effective timing for the drug administration after exposure to hyperthermia. Both topoisomerase II contents and topoisomerase II activity were significantly increased in WiDr cells 3 to 12 h after heat stress at 43 degrees C for 1 h, in comparison with those immediately after the heat stress. Cytotoxicity by VP-16 was most significantly enhanced 3 to 12 h after exposure to 43 degrees C for 1 h, but no synergistic effect was observed when the drug was administered immediately after the heat stress. A combination of VM-26 with heat stress, but not that of a topoisomerase I-targeting camptothecin derivative (CPT-11), or vincristine, showed a synergistic cytotoxic effect on WiDr cells. VP-16 alone induced cellular accumulation at the G2 + M phase, whereas the combination of VP-16 and heat stress further increased the cell population at the G2 + M phase, and decreased S-phase cells. A possible application of the combination of VP-16 and hyperthermia in clinical use is discussed.
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PMID:Biomodulation by hyperthermia of topoisomerase II-targeting drugs in human colorectal cancer cells. 856 2

NU/ICRF 505 is a tyrosine conjugate of anthraquinone modified at the C terminus of the amino acid as an ethyl ester and it stabilizes topoisomerase I (topo I)-cleavable complexes. It is active in vitro against a panel of human cell lines, including drug-resistant variants, and possesses in vivo antitumour activity. NU/ICRF 505 was rapidly metabolized in nude mice to a product which represented the sole detectable form of the drug present in plasma and a chemosensitive human xenograft (HT-29 colon cancer). The metabolite (codenamed NU/ICRF 505/M) was purified, characterized by mass spectrometry and UV-visible spectroscopy, and shown to be the free amino acid produced by hydrolysis of the ethyl ester bond. NU/ICRF 505/M stabilized topo I-cleavable complexes in assays with human enzyme and was equipotent to the parent drug. Nonetheless, the metabolite was inactive in vitro against a panel of human tumour cell lines (including HT-29) and was not significantly taken up into cells in drug-uptake studies. Levels of the metabolite measured in the HT-29 xenograft after administration of a therapeutic dose of NU/ICRF 505 (25 mg/kg i.p.) remained above 1 microM for 6 h, and exceeded 10 microM at 10 min and 2 h. These data suggest that NU/ICRF 505 is a prodrug in nude mice for its topo-active metabolite NU/ICRF 505/M which accumulates in the tumour.
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PMID:Characterization of the major metabolite of the novel topoisomerase I inhibitor NU/ICRF 505. 876 30

Previous cell line comparisons indicated that neither S-phase fraction nor topoisomerase I (top1) levels are sufficient to predict camptothecin (CPT) cytotoxicity (F. Goldwasser el al., Cancer Res., 55: 2116-2121, 1995.). To identify new determinants for CPT activity, two mutant p53 human colon cancer cell lines, SW620 and KM12, that were previously reported to have similar top1 levels and differential sensitivity to CPT were studied. No difference in the kinetics of top1-mediated DNA single-strand breaks or DNA synthesis inhibition were observed after 1 h exposure to 1 microM CPT. Pulse-labeling alkaline elution showed deficiency of damaged replicon elongation in the more sensitive SW620 cells. Consistentiy, flow cytometry analyses showed that KM12 was arrested in G2, whereas SW620 cells were irreversibly blocked in S phase. Aphidicolin protection was minimal in KM12 and more pronounced in the more sensitive SW620 cells. Thus, CPT appears to have two cytotoxic mechanisms, one protectable by aphidicolin and present in SW620 and the other not protectable by aphidicolin and common to both cell lines. SW620 exhibited also a greater capacity to break through the G2 checkpoint after DNA damage. Consistently, SW620 cells failed to down-regulate cyclin B-cdc2 kinase activity, whereas KM12 cells down-regulated cyclin B/cdc2 kinase activity within 30 min to 20 % of control level after CPT treatment. Analysis of the 7 human colon carcinoma cell lines of the NCI Anticancer Drug Screen showed that defects in replicon elongation and G2 breakthrough capability correlate with sensitivity to CPT. Our results suggest that misrepair of damaged replicons and/or alterations in DNA damage checkpoints is critical to defining chemosensitivity to CPT-induced top1-cleavable complexes and that CPT appears to have two cytotoxic mechanisms, one protectable by aphidicolin, and the other not.
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PMID:Correlations between S and G2 arrest and the cytotoxicity of camptothecin in human colon carcinoma cells. 881 37

The glucose-regulated stress response in mammalian cells is characterized by the increased synthesis of glucose-regulated proteins (GRPs). In this study, we found that GRP-inducing conditions in culture led to induction of resistance to the topoisomerase I-targeted drug camptothecin in human colon cancer HT-29 and ovarian cancer A2780 cells. The induction of camptothecin resistance was accompanied by decreased levels of camptothecin-induced cleavable complexes, as measured by a topoisomerase I band depletion assay. However, topoisomerase I protein levels were the same in both stressed and non-stressed cells. Furthermore, when isolated nuclei from stressed and non-stressed cells were treated with camptothecin, similar levels of cleavable complexes were obtained, suggesting that the activity of topoisomerase I did not change in stressed cells. In contrast, intracellular accumulation of camptothecin decreased in stressed cells. Our results indicate that stress-induced camptothecin resistance could be explained by reduced camptothecin accumulation, leading to decreased numbers of cleavable complexes, without quantitative or qualitative changes in topoisomerase I levels. In addition, cell cycle analysis revealed that the GRP-inducing treatments resulted in an accumulation of G1/G0-phase cells. As camptothecin shows an S-phase-specific cytotoxicity, the G1/G0-phase accumulation is another mechanism for camptothecin resistance. Since a glucose-regulated response is produced by hypoxia and nutrient deprivation that occur naturally in solid tumors, the resistance observed here can occur in some solid tumors and can be an obstacle to chemotherapy.
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PMID:Glucose-regulated stresses induce resistance to camptothecin in human cancer cells. 890 83

Camptothecin (CPT) traps covalent DNA topoisomerase I-linked DNA single-strand breaks (cleavable complexes). To determine the differences in DNA damage signalling leading to differential sensitivity to CPT, two human colon cancer cell lines, SW620 and KM12, with nonfunctional p53 and the same level of topoisomerase I cleavable complex formation but differential sensitivity to CPT (Cancer Res. 56:4430-7; 1996) were studied. The levels of mRNA expression of DNA damage-inducible or death-related genes were measured at different times after CPT treatment. KM12 cells exhibited 3-fold higher basal levels of BCL-2 mRNA. Consistently, secondary DNA fragmentation, quantitated using a filter elution assay, was detected 24 h later and was 2-4-fold lower in KM12 cells than in SW620 cells. No induction of BAX was detected in either cell line. Consistent with the absence of functional p53, p21CIP1/WAF1 and GADD45 genes were not induced within the first 24 h. However, in SW620 cells, both mRNA levels were increased more than 10-fold at 48 h. The BCL-2-related gene MCL-1 and topoisomerase II mRNA were induced at 24 h, and topoisomerase I mRNA levels increased 3-fold at 48 h, only in SW620 cells. We conclude that cellular response to CPT-induced DNA damage can involve p53-independent pathways leading to the induction of p53-effector genes. Induction of these genes at the onset of apoptosis is associated with CPT sensitivity.
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PMID:Differential GADD45, p21CIP1/WAF1, MCL-1 and topoisomerase II gene induction and secondary DNA fragmentation after camptothecin-induced DNA damage in two mutant p53 human colon cancer cell lines. 893 95

Colorectal cancer affects around 5% of the population in Westernised countries and is associated with a high level of morbidity and mortality. Overall, around 50% of patients can expect to be fully cured by surgery, along with recent improvements in survival due to the use of adjuvant therapy. However, in patients who develop metastatic disease, the prognosis is poor, and the appropriateness of anticancer chemotherapy in such patients has been controversial. Nevertheless, there is increasing evidence that chemotherapy can extend life expectancy in colorectal cancer and that in metastatic disease patients achieve a significant benefit from early rather than late chemotherapy. For first-line treatment of metastatic colorectal cancer, the best available regimens have been those which include 5-fluorouracil (5-FU) and folinic acid; a meta-analysis of nine randomised clinical studies of such regimens produced a mean response rate of 23%. However, in those who fail or relapse, there has been no established second-line alternative. The development of CPT-11 (Campto, irinotecan), a specific inhibitor of topoisomerase I, represents a significant advance in the management of colorectal cancer. Following encouraging observations of sustained activity in colon cancer cell lines, including those having the MDR phenotype, clinical studies of CPT-11 monotherapy in both chemotherapy-naive and pretreated patients with advanced colorectal cancer demonstrated response rates at least equivalent to those achieved with first-line 5-FU/folinic acid combination therapy. This indicates that CPT-11 does not exhibit cross-resistance with 5-FU, making it the first effective second-line agent in this setting. Further studies are ongoing to define the optimum dosage schedule for CPT-11 and to assess the utility of CPT-11 as a single agent in second-line therapy, or combined with 5-FU and other anticancer agents as first-line therapy. In conclusion, CPT-11 offers a different cytotoxic approach that may complement the use of 5-FU/folinic acid in colorectal cancer in the future.
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PMID:Current status of colorectal cancer: CPT-11 (irinotecan), a therapeutic innovation. 894 58

Topotecan (Hycamtin; SmithKline Beecham Pharmaceuticals, Philadelphia, PA), a camptothecin analog, is a novel and specific inhibitor of the nuclear enzyme topoisomerase I. In preclinical studies, topotecan demonstrated significant in vitro activity in a variety of solid tumor explants derived from colorectal, breast, ovarian, renal cell, non-small cell lung cancer, and gastrointestinal sources. Notable activity was also demonstrated in vivo in a wide range of animal tumor models. A large number of phase I studies with topotecan have been conducted since 1992 in both adults and children with a broad range of refractory malignancies and as many as 14 different dosing schedules. Complete, partial, or minor responses were demonstrated in patients with recurrent or refractory neuroblastoma, non-small cell lung cancer, small cell lung cancer, ovarian cancer, breast cancer, colon cancer, esophageal cancer, renal cell carcinoma, and squamous cell carcinoma. The antitumor activity of topotecan in these phase I evaluations was associated more often with frequent or continuous dosing schedules compared with less frequent or short exposure schedules. Maximum tolerated doses were predominantly dependent on the dosing schedule used. Myelosuppression was the major dose-limiting toxicity across all schedules, and nonhematologic toxicities were generally mild. Data from phase I studies have provided valuable information about antitumor responses, maximum tolerated doses, and dose-limiting toxicities associated with different dosing schedules. Based on this information, there was substantial enthusiasm for further evaluating topotecan in a wide range of cancer patients in phase II studies.
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PMID:Review of phase I clinical studies with topotecan. 942 56


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