Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topoisomerase (topo) I and II are nuclear enzymes which are novel targets of cancer chemotherapy. A new camptothecin (CPT) analog, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyl-oxy-CPT (CPT-11), is a topo-I inhibitor with a higher activity and less toxicity than CPT. To investigate topo-I and -II-targeting chemotherapy in an in vivo model, we studied the effect of sequential or co-treatment using CPT-11 and adriamycin (ADR) a topo-II inhibitor, in 6 human tumor xenografts (2 esophageal, 2 gastric and 2 colon tumor lines). In sequential treatment, adriamycin was administered i.v. 24 hr after CPT-11 treatment, and no antagonistic effect of this treatment schedule was observed. ADR cytotoxicity was potentiated significantly by CPT-11 pretreatment in the case of 2 esophageal and 2 gastric tumor lines and 1 colon tumor line. On the other hand, co-treatment abolished the sensitivity to CPT-11 and ADR in all 6 tumor lines. Moreover, CPT-11 did not significantly enhance the cytotoxicity of other agents tested, including mitomycin C (MMC) and cisplatin (CDDP). Flow cytometry and dot-blot analyses showed that CPT-11 pretreatment induced an increase in the S-phase cell population with an increase of topo-II mRNA expression after 24 and 48 hr, respectively, in the esophageal and colon tumor lines. These results suggest that CPT-11 can modulate topo-11 levels to enhance the effect of topo-II inhibitors in some human tumors, and this suggests a new clinical method of topo-I and -II targeting chemotherapy for human solid tumors.
 ...
PMID:Experimental studies on biochemical modulation targeting topoisomerase I and II in human tumor xenografts in nude mice. 131 63

RNA/PCR quantitation method was developed to determine DNA Topoisomerase I(Topo I)-specific mRNA in order to study its gene expression in CPT-11 sensitive, acquired- or native-resistant human pancreatic tumor cell lines. The results were supported by Northern blotting and Western blotting analyses. Acquired-resistant cells have shown decreased levels of Topo I mRNA, compared with their parental cells. On the contrary, in the wild type cells no correlation was shown between sensitivity and gene expression. On the other, specific Topo I activity of the native resistant cell lines was fairly lower than that of sensitive cell lines, suggesting that immunoreactive Topo I protein contains low levels of active form enzyme which could be targets of CPT-11 in these native-resistant ones. Finally, the different mechanisms might be operative between acquired- and native-resistant tumor cells.
 ...
PMID:Differential expression of DNA topoisomerase I gene between CPT-11 acquired- and native-resistant human pancreatic tumor cell lines: detected by RNA/PCR-based quantitation assay. 131 26

In the course of our study to determine the cross-sensitivity between CPT-11 and its active metabolite, SN-38, we found a SN-38-resistant human pancreatic tumor cell line, QGP-1N, which shows sensitivity to CPT-11. The IC50 of SN-38 was 152 times greater for QGP-1N than for SUIT-2, also a human pancreatic tumor cell line, whose IC50 of CPT-11 was similar to that for QGP-1N. The uptakes of CPT-11 and SN-38 and the intracellular conversion of CPT-11 to SN-38 could not explain the difference in sensitivity. DNA synthesis of QGP-1N cells was inhibited by CPT-11 which did not affect that of SUIT-2, while SN-38 inhibited the DNA synthesis of SUIT-2 at lower concentrations than that of QGP-1N. The inhibition test of topoisomerase I catalytic activity by CPT-11 or SN-38 revealed no difference in the biochemical properties of the topoisomerase I enzymes to the compounds between these two cell lines. These results indicate that CPT-11 should have its own inhibitory effect on DNA synthesis through a yet unknown mechanism in QGP-1N cells, although SN-38 plays an essential role in the antitumor activity of CPT-11 in SUIT-2 cells. In some cases, the antitumor effect of CPT-11 might be consequent not only on SN-38 but also on CPT-11 itself.
 ...
PMID:Camptothecin analog (CPT-11)-sensitive human pancreatic tumor cell line QGP-1N shows resistance to SN-38, an active metabolite of CPT-11. 132 48

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

Significant prolongation of survival time among the patients with advanced ovarian cancer has been brought under the development of surgery and chemotherapy, but even those with clinical remission shows sometimes recurrence. For the recurrent ovarian cancer patients at present there are no definite strategy to treat the recurrent cases. Under these circumstance, we have reviewed the current treatment of cytoreductive surgery and chemotherapy for the recurrent cases. 1) surgical treatment Generally, in the cases of recurrent ovarian cancer, cytoreductive surgery is required to minimize the residual tumour in the abdomen. But sometimes we can find the distant metastasis including liver, lung, and lymph node. This means that surgery is not sufficient for control of recurrent tumor. Further adjuvant chemotherapy will be required to control metastatic tumors. 2) chemotherapy After the detail assessment of the initial treatment of cases, at first we should think about retreatment with CDDP-based regimen and secondly about dose-intensification of CDDP or CBDCA for the CDDP-resistant cases. And as combination regimens, topoisomerase inhibitors, etoposide or CPT-11 are also preferable to use, alkylating agents such as ifosfamide, 5-fluorouracil, and some current trials with new drug, taxol are effective for recurrent cases. In conclusion, further active chemotherapy using platinum compounds, topoisomerase inhibitors, taxol will be achieved for the control of the recurrent cases of ovarian cancer.
 ...
PMID:[Treatment of recurrent ovarian cancer]. 135 32

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

The co-operative effects of recombinant human tumor necrosis factor (rH-TNF) and CPT-11, a new derivative of camptothecin, against the proliferation of human gynecologic tumor cell lines were examined in vitro. The ishikawa cells were responsive to rH-TNF, the HHUA cells exhibited a minimal degree of responsiveness to rH-TNF, and the HeLa S3 and Caov-3 cells were unresponsive to rH-TNF. The HHUA, Ishikawa and Caov-3 cells were responsive to CPT-11, and the HeLa S3 cells were relatively sensitive to CPT-11 cytotoxicity. In all four cell lines, rH-TNF at clinically achievable concentrations exhibited synergy with CPT-11. The combination therapy of rH-TNF and CPT-11 will be a new approach against gynecologic cancers.
 ...
PMID:Augmentation of antiproliferative activity of CPT-11, a new derivative of camptothecin, by tumor necrosis factor against proliferation of gynecologic tumor cell lines. 180 90

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)
 ...
PMID:[Preclinical trials from the standpoint of clinical trials]. 185 17

The antitumor effects of the camptothecin (CPT) derivative CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin , were tested on human tumor xenografts in nude mice. CPT-11 showed antitumor activity higher than that of Adriamycin, 5-fluorouracil, or futraful, with little or no reduction of body weight being observed in the mice. The growth of colon adenocarcinoma Co-4 was significantly inhibited after a single i.v. injection of CPT-11 at 25, 50, or 100 mg/kg. The single i.v. injection was also significantly effective against mammary carcinoma MX-1 and gastric adenocarcinoma St-15. All of the mice bearing MX-1 tumors were cured by the administration of CPT-11 every 4 days for a total of three treatments at a total dose of 200 mg/kg given i.v. or of 400 mg/kg given p.o. Three i.v. or oral treatments were also effective against Co-4, St-15, gastric adenocarcinoma SC-6, and squamous-cell lung carcinoma QG-56. To achieve the same efficacy attained by i.v. injection, however, oral doses 2-4 times higher than the i.v. doses were required. When the total dose was fixed at 100 mg/kg, a triple i.v. injection was most effective, followed by a single i.v. injection and, finally daily p.o. administration for 10 days. Although SN-38 (7-ethyl-10-hydroxycamptothecin), a metabolite of CPT-11, showed much stronger cytotoxic activity in vitro than did CPT-11, its antitumor effects were similar, if not inferior, to those of CPT-11 in vivo at the same dose level. CPT-11 was converted into SN-38 by human tumors, but the sensitivity of these tumors to CPT-11 in vivo was independent of their ability to produce SN-38. These results suggest that CPT-11 may be clinically effective, depending on the schedule of administration, but that its effectiveness is not related to the ability of the tumor to produce SN-38.
 ...
PMID:Antitumor activity of a camptothecin derivative, CPT-11, against human tumor xenografts in nude mice. 185 76

A clinical study of weekly administration of CPT-11, a semi-synthetic derivative of Camptothecin, was performed in patients with advanced lung cancer to determine the optimal dose for a weekly single dose schedule. Sixteen out of 19 patients enrolled were evaluable. The starting dose was 50 mg/m2 and gradually escalated to 100, 125 and 150 mg/m2. CPT-11 was given by intravenous infusion for 90 minutes every week. The maximum tolerated dose for this schedule was estimated to be 125 mg/m2. The dose-limiting toxicity was leukopenia with median nadir of 2,900/mm3, median day to nadir of 21, and median day to recovery of 7. Other major toxicity was gastrointestinal upset, but was mild and tolerable. Objective tumor responses were observed in four patients, three with non-small cell carcinoma and one with double cancer (small and non-small cell carcinoma). The responding patients were treated at a dosage of 100 mg/m2 or more. The recommended dose for a phase II study is considered to be 100 mg/m2 iv infusion for a weekly single-dose schedule.
 ...
PMID:[A phase I study of weekly administration of CPT-11 in lung cancer]. 215 68


1 2 3 4 5 6 7 8 9 10 Next >>