Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An early phase II study of CPT-11 was carried out in patients with primary lung cancer in 15 institutions throughout Japan. The efficacy and safety of CPT-11 were studied at 200 mg/m2 based on the results of the previous phase I study. Thirty-eight of 52 enrolled patients were eligible. CPT-11 proved to be effective for primary lung cancer. The response rates were 20.0% (7/35) for non-small cell lung carcinoma and 33.3% (1/3 for small cell lung carcinoma. Hematological toxicities included leukopenia (less than or equal to 3,000) in 44.7% of the patients. Other major toxicities were nausea/vomiting (greater than or equal to grade 2) in 50.0% and diarrhea (greater than or equal to grade 2) in 47.4%.
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PMID:[An early phase II study of CPT-11 in primary lung cancer]. 184 91

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.
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PMID:Antitumor activity of a camptothecin derivative, CPT-11, against human tumor xenografts in nude mice. 185 76

With the purpose of obtaining more potent and less toxic camptothecin (CPT) analogs, we prepared many derivatives of CPT. Among them, 7-ethyl-CPT (SN 22) and 7-ethyl-10-hydroxy-CPT (SN 38) showed strong antitumor activity with less toxicity. They were, however, insoluble and when they were made soluble, their activity was markedly diminished, as a result of cleavage of the delta-lactone ring. We therefore attempted to make soluble derivatives without breaking the delta-lactone ring and obtained 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy-CPT (CPT-11), which showed very strong antitumor activity by i.p., i.v. or p.o. administration against the ascites type of L1210 leukemia, P388 leukemia, sarcoma 180, Meth A fibrosarcoma, B16 melanoma, Ehrlich carcinoma and MH134 hepatoma and the solid type of sarcoma 180, Meth A fibrosarcoma, Lewis lung carcinoma, C3H/HeN mammary carcinoma, Ehrlich carcinoma and MH134 hepatoma. The antileukemic activity of CPT-11 against L1210 was much higher than that of adriamycin. The acute toxicity of CPT-11 was extremely low, particularly in the case of oral administration, the LD50 being 765.3 mg/kg, 22 times greater than that of CPT-Na.
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PMID:[Antitumor activity of new derivatives of camptothecin]. 356 96

The search for new water-soluble analogues of camptothecin (CPT) with higher activity and less toxicity has led to the development of a novel compound, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11), which showed significant antitumor activity against a broad spectrum of experimental tumor models by i.p., i.v., or oral administration. When its activity against L1210 was compared with that of CPT and known derivatives, CPT-11 was most effective, giving the highest maximum increase in life span (ILS) and showing good activity over a wide dose range. The antitumor activity of CPT-11 was shown against tumors not only in the ascites form but also in the solid form. Included among the more susceptible murine tumors are S180, Meth A fibrosarcoma, Lewis lung carcinoma, Ehrlich carcinoma, MH134 hepatoma, mammary carcinoma of C3H/HeN mice, L1210, and P388 leukemia. Probable cures of these tumors were induced frequently by CPT-11. The antitumor activity of CPT-11 against i.p.-implanted L1210 was superior to that of Adriamycin in maximum ILS, the number of cured mice, and the therapeutic ratio. CPT-11 at a dose of 100 mg/kg produced an ILS in excess of 300% with five of six mice surviving tumor free, and effected 100% tumor regression at 200 mg/kg, whereas the optimum dose of Adriamycin, 12.5-25 mg/kg, brought about 114-129% ILS with one of six mice surviving. The acute toxicity of CPT-11 was extremely low, particularly in the case of oral administration. CPT-11 is expected to be clinically useful.
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PMID:Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothec in, a novel water-soluble derivative of camptothecin, against murine tumors. 366 96

Chemotherapy is rather ineffective in non-small cell lung cancer. However, in the last few years, a number of new anticancer agents have been developed which have definite activity in this disease. Among them are the taxanes and CPT-11, drugs with novel mechanisms of action, new antimetabolites (edatrexate and gemcitabine), and a new vinca alkaloid (vinorelbine). Furthermore, in the near future, the better understanding of lung cancer biology will help in devising new treatment strategies.
Lung Cancer 1995 Apr
PMID:New drugs in non-small cell lung cancer. An overview. 755 24

Camptothecin is a natural product derived from the Oriental tree Camptotheca acuminata which has shown activity in a number of experimental tumors. Its clinical development was halted in the early-70s owing to its unpredictable and formidable toxicities. Two water-soluble camptothecin analogs have been synthesized recently and are currently in clinical trials: topotecan and CPT-11. Camptothecin and its derivatives are unique in that they represent the only family of topoisomerase I inhibitors. Topoisomerase I is a nuclear enzyme which modulates the topological structure of DNA by making transient single-stranded breaks. Pre-clinical studies have shown that CPT-11 and topotecan possess high and broad antitumor activity against a variety of experimental tumors including both non-small cell lung cancer (NSCLC) and small cell lung cancer. Lack of cross-resistance with most classical anticancer agents has been also demonstrated. Phase I studies have identified neutropenia to be the dose-limiting toxicity for topotecan while, for CPT-11, either neutropenia or diarrhoea were dose-limiting. Maximum Tolerated Doses (MTD) of both agents are greatly dependent upon the schedule used. A Phase II Japanese study of CPT-11 in advanced untreated NSCLC has been recently published. Given at the dose of 100 mg/m2 as a 90-min infusion, CPT-11 produced a 32% objective response rate out of 72 assessable untreated patients. Similar studies are in progress with topotecan. The same Japanese group has completed Phase I-II studies on the combination of CPT-11 with cisplatin. The optimal dose of CPT-11, which can be safely combined with cisplatin 80 mg/m2, was found to be 60 mg/m2.(ABSTRACT TRUNCATED AT 250 WORDS)
Lung Cancer 1995 Apr
PMID:Camptothecin analogues in the treatment of non-small cell lung cancer. 755 27

Recently there has been a number of new active drugs which have been identified for treating patients with SCLC. These drugs include paclitaxel, docetaxel, CPT-11, topotecan and gemcitabine. The range of response rates are as follows for each of the drugs given: (1) to previously untreated patients: paclitaxel (34-41%), topotecan (39%) and gemcitabine (30%), and (2) to previously treated patients: docetaxel (28%), CPT-11 (47%) and topotecan (35%). Further studies with these new drugs utilized in combination chemotherapeutic regimens are needed to define the role of these agents in the treatment of patients with SCLC.
Lung Cancer 1995 Jun
PMID:New drugs for treating small cell lung cancer. 755 57

The projected cure rate for patients who develop lung cancer in 1993 is only 13%. The majority of these patients have metastatic disease at the time of diagnosis, and are therefore ineligible for curative surgery. Among the minority of patients who undergo surgical therapy with curative intent, the majority experience relapse in metastatic sites. Patients with metastatic disease cannot be cured with currently available therapies. Recent randomized studies suggest that cisplatin-based chemotherapy regimens can prolong survival in patients with metastatic non-small cell lung cancer and small cell lung cancer. It was thus logical to evaluate cisplatin-based chemotherapy in early disease stages. Many randomized studies have compared radiation therapy alone with radiation plus cisplatin-based chemotherapy in locally advanced, inoperable, stages IIIA and IIIB non-small cell lung cancer. Most, but not all, of these studies show a survival benefit for the combined-modality approach. Although the improvement in median length of survival in these studies is modest, long-term survival rates are often doubled or tripled. The optimal chemoradiotherapy combination is unknown. Fewer randomized trials have evaluated cisplatin-based chemotherapy as an adjuvant to surgery in operable stages I through IIIA disease. A trial of the Lung Cancer Study Group comparing postoperative cyclophosphamide/doxorubicin/cisplatin with immunotherapy in stages II and IIIA adenocarcinoma and large cell carcinoma showed a small survival advantage for the chemotherapy. A European postoperative randomized study comparing cisplatin-based chemotherapy with no therapy also showed a survival advantage for chemotherapy, as did a small ongoing study from M.D. Anderson Cancer Center (Houston, TX) with preoperative chemotherapy. However, there are many negative randomized studies evaluating postoperative chemotherapy, especially with non-cisplatin-based regimens, and further studies are obviously needed. Many new agents have produced exciting preliminary results. Response rates in excess of 20% were reported for paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), irinotecan (CPT-11), topotecan, and gemcitabine. Studies in the next few years will help to define the ultimate role of these agents. Further developments in understanding the biology (and molecular biology) of lung cancer are leading to preclinical studies of antigrowth factors and genetic therapy.
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PMID:The treatment of non-small cell lung cancer: current perspectives and controversies, future directions. 805 74

Paclitaxel-2-ethylcarbonate (PC) is a prototype for a family of paclitaxel prodrugs that have significant levels of antitumor activities in rodent models for human cancer. In this study, an enzyme responsible for the conversion of PC to paclitaxel was purified from rat serum. N-terminal amino acid sequence analysis indicated that the isolated enzyme was rat serum carboxylesterase. This enzyme was shown to significantly enhance the cytotoxic activities of both PC and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), a water-soluble analogue of camptothecin, on lung carcinoma and melanoma cell lines. Rat serum carboxylesterase may have applications for the site-specific delivery of anticancer drugs to tumor masses.
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PMID:The role of rat serum carboxylesterase in the activation of paclitaxel and camptothecin prodrugs. 860 86

Irinotecan (CPT-11) is a semi-synthetic derivative of camptothecin currently in clinical trials. In vitro, CPT-11 presented preferential cytotoxicity toward some solid tumor cells (mouse colon 38 and pancreas 03; human pancreas MIA PaCa-2) as compared to leukemia cells (L1210), whereas SN-38, a metabolite of CPT-11, was not solid tumor selective. In vivo, schedule of administration studies in P388 leukemia and mammary adenocarcinoma 16/C (MA16/C) showed that CPT-11 was not markedly schedule dependent. In order to determine its spectrum of anticancer activity, CPT-11 was evaluated against a variety of mouse and human tumors. The end points used were total log cell kill (Lck) for solid tumors and increase in life span (% ILS) for leukemia. Intravenous CPT-11 was found highly active against both early and advanced stage pancreatic ductal adenocarcinoma 03 (P03), with 60% long-term survivors and 100% complete regressions, respectively. Other responsive tumors included: colon adenocarcinomas 38 and 51 (both 1.0 Lck); MA16/C (3.4 Lck); MA13/C (1.0 Lck); human Calc18 breast adenocarcinoma (2.8 Lck); Glasgow osteogenic sarcoma (1.8 Lck); Lewis lung carcinoma (1.4 Lck); B16 melanoma (1.4 Lck); P388 leukemia (170% ILS) and L1210 leukemia (64% ILS). Of interest, CPT-11 was active against tumors with acquired resistance to vincristine (P388/Vcr), to doxorubicin (P388/Dox) and to docetaxel (Calc18/TXT). CPT-11 was also found highly active after oral administration in mice bearing P03 and MA16/C tumors. Pharmacokinetic evaluations performed i.v. at the highest non-toxic dosage in mice bearing P03 tumors revealed CPT-11 peak plasma concentrations (Cmax) of 8.9 micrograms/ml and a terminal half-life of 0.6 h. The metabolite SN-38 plasma concentrations presented a Cmax of 1.6 micrograms/ml and a terminal half-life of 7.4 h. Although the CPT-11 tumor levels were similar to the plasma concentrations for early time points, drug levels decreased more slowly in the tumor compared to plasma (half-life, 5.0 h). SN-38 tumor levels reached concentrations in the range of 0.32-0.34 micrograms/g and decayed with a half-life of 6.9 h. No significant difference in plasma or tumor pharmacokinetics of either CPT-11 or SN-38 were noted after one or five daily i.v. injections. Overall, these data show that CPT-11 has good activity in experimental models, when administered both by the i.v. and the oral routes. Compared to humans, a similar schedule of administration independence was observed and similar CPT-11 levels could be reached at efficacious dosages although metabolite SN-38 levels were found higher in mice.
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PMID:Experimental antitumor activity and pharmacokinetics of the camptothecin analog irinotecan (CPT-11) in mice. 882 13


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