Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topoisomerase I represents a unique new target that can be exploited for development of new antineoplastic agents. There are now two new topoisomerase I inhibitors that are in early clinical trials that have generated a tremendous amount of interest. Topotecan (SKF 104864-A) is a topoisomerase I inhibitor that has been explored in phase I trials using a variety of dosages and schedules. The dose-limiting toxicity of the agent is neutropenia. Other toxicities include alopecia, very mild nausea and vomiting, anemia, and occasional fever. Responses have already been noted in patients with advanced, refractory ovarian cancer and non--small-cell lung cancer. The drug is currently undergoing intense phase II testing. Irinotecan (CPT-11) is also a topoisomerase I inhibitor, which has already undergone extensive phase I and early phase II clinical testing in both Japan and the United States. Dose-limiting toxicities of the agent have included neutropenia and diarrhea. Responses have been noted in patients with refractory colorectal cancer, non--small-cell lung cancer, lymphoma, ovarian cancer, head and neck cancer, pancreatic cancer, and breast cancer. There is no doubt both of these agents will be important additions to our chemotherapy armamentarium.
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PMID:Clinical trials with the topoisomerase I inhibitors. 133 79

Irinotecan (CPT-11), a new derivative of camptothecin, showed schedule-dependent antitumor activity and toxicity in preclinical animal studies. We carried out a phase I study of weekly CPT-11 infusion, which indicated that the recommended dose for phase II studies was 100 mg/m2. In a phase II trial, CPT-11 achieved a response rate of 32% for non-small cell lung cancer (NSCLC). In two phase II trials, CPT-11 achieved objective response rates of 37% and 47% for small cell lung cancer (SCLC). The high activity of CPT-11 in these phase II studies suggested that the next rational step was to investigate combination chemotherapy. The first phase I trial of CPT-11 combined with cisplatin achieved an encouraging response rate of 54% in 27 patients with previously untreated NSCLC, and the recommended schedule for phase II studies was 60 mg/m2 of CPT-11 (days 1, 8, and 15) plus 80 mg/m2 of cisplatin (day 1) given at 4-week intervals. Given the high single-agent activity of CPT-11 against SCLC and NSCLC, a regimen with a higher dose of this agent and a lower dose of cisplatin seemed likely to be more effective. In the second trial, the cisplatin dose was accordingly reduced from 80 to 60 mg/m2, and the recommended dose of CPT-11 was concluded to be 80 mg/m2. Thus, reduction of the cisplatin dose to 60 mg/m2 allowed the safe administration of CPT-11 at 80 mg/m2 (33.3% dose intensification compared with the original regimen). The most recent trial of this combination with recombinant human granulocyte colony-stimulating factor (rhG-CSF) support demonstrated that the recommended dose is 80 mg/m2 of CPT-11 and 80 mg/m2 of cisplatin. Thus, we could raise the CPT-11 dose 33% above that given in the original regimen while maintaining the original cisplatin dose by the use of rhG-CSF support. Further trials are needed to evaluate the effect of CPT-11 given in combination with other active agents for the treatment of lung cancer.
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PMID:Clinical studies of irinotecan alone and in combination with cisplatin. 807 18

Anticancer drug development has recently shifted in part to development of more innovative anticancer agents. The increasing knowledge of the pathogenetic mechanisms involved in cancer cell growth has enabled the introduction of drug screening that is more mechanism-based. The realization that new targets should be preferentially evaluated as sites for anticancer drug treatment has led to the introduction of drugs such as the taxanes. Following this logic, several new drugs are being developed. Minor groove-binding agents such as carzelesin and oral platins lacking organ toxicity, such as JM216, have recently entered clinical studies. The activity of gemcitabine is a result of its being a cytidine analogue and being competitively incorporated by DNA; the drug has shown interesting activity in non-small-cell lung cancer and, although registration is imminent, issues regarding the optimal dose and administration schedule have yet to be resolved. Tomudex is a thymidylate synthase inhibitor with interesting activity in colorectal cancer. Activity in colorectal cancer is also of interest for irinotecan, the first clinically applied topoisomerase I inhibitor, an enzyme that is another example of a new target for anticancer drugs. Irinotecan has produced consistent response rates of 20-30% in six different studies in colorectal cancer. The other topoisomerase I inhibitor that is in the advanced stage of development is topotecan. This drug has shown activity in second-line chemotherapy for ovarian cancer and small-cell lung cancer. Another interesting feature of topotecan is the availability of an oral formulation with consistent bioavailability. Drugs interfering with cellular signal transduction, such as the protein kinase C inhibitors, are in the development spotlight. Finally, the use of old drugs in new ways, such as immunoconjugates of doxorubicin, holds promise for the near future.
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PMID:New promising anticancer agents in development: what comes next? 876 8

Non-small-cell lung cancer (NSCLC) will increasingly come under better control as the current approaches to therapy are more broadly employed and as new therapies are deployed against recently elucidated molecular pathways. In the United States, real progress is finally being made in decreasing tobacco consumption and in lung cancer incidence. The traditional chemotherapeutic compounds that became available earlier this decade (paclitaxel [Taxol], docetaxel [Taxotere], gemcitabine [Gemzar], vinorelbine [Navelbine], irinotecan [Camptosar], topotecan [Hycamtin], and edatrexate) have all been tested as single agents and as doublets with cisplatin (Platinol) and carboplatin (Paraplatin). Paclitaxel with cisplatin or carboplatin and vinorelbine, docetaxel, or gemcitabine with cisplatin have all demonstrated significant activity that now appears clearly better than the prior standard therapy of etoposide (VePesid)/cisplatin. Phase III studies sorting out their benefit relative to each other should be completed in the next 1 to 2 years. To date, no triplet therapy appears better than the corresponding doublet. Non-platinum-containing doublets are just completing their first round of assessments. Aside from new drugs and applications, the use of "small" molecules to inhibit either signal transduction pathways or gene activation is likely to accelerate. Most of the newer chemotherapeutic agents can be interdigitated with radiation and surgery, although evaluations into sequence and dose issues continue. The superior outcomes seen with the newer regimens should translate to the adjuvant and preoperative or preradiotherapy settings relatively quickly. It is now clear that NSCLC is as responsive to therapy as small-cell lung cancer (SCLC) and that outcomes are superior for NSCLC. The enthusiasm for treating SCLC displayed by nononcologists and nonthoracic medical oncologists should be shared for NSCLC.
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PMID:Future directions in non-small-cell lung cancer: a continuing perspective. 951 20

Although small-cell lung cancer (SCLC) represents only 20% of all lung cancer cases in the United States, it is the most lethal subtype. Combination chemotherapy unequivocally offers the best chance for improved survival in SCLC. Either PE (platinum plus etoposide) or CAV (cyclophosphamide, Adriamycin, and vincristine) is a reasonable first-line therapy. Alternating PE with CAV does not appear to be significantly superior to PE or CAV alone. Increasing dose intensity, although sometimes associated with higher response rates, does not appear to significantly improve survival and should not be used outside of a clinical study. Several new agents with novel mechanisms of action show promise in treating SCLC. These include: gemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere), topotecan (Hycamtin), and irinotecan (Camptosar). Given the poor survival and response rates in relapsed patients and the chemoresponsiveness of SCLC, patients with newly diagnosed extensive disease should be encouraged to enroll in phase I or II trials. Thoracic radiotherapy confers a small survival advantage in limited-stage SCLC patients. Although prophylactic cranial irradiation does not significantly improve survival, it does reduce central nervous system (CNS) recurrences with minimal long-term sequelae. Surgery should be considered only for: (1) resection of a solitary pulmonary nodule, which must be followed by adjuvant chemotherapy; and (2) resection of an unresponsive chest tumor, which may harbor a non-small-cell lung cancer component.
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PMID:Small-cell lung cancer: treatment progress and prospects. 959 76

Irinotecan (CPT-11) is a semisynthetic camptothecin derivative with a broad spectrum of anti-tumour activity. Carboxylesterase (CE) catalyses the conversion of CPT-11 to SN-38 (7-ethyl-10-hydroxycamptothecin), the active form of CPT-11. The antiproliferative effects of CPT-11 and SN-38, CE-activity and topoisomerase I protein expression were investigated in five human small-cell lung cancer (SCLC) cell lines and four human non-small-cell lung cancer (NSCLC) cell lines. Antiproliferative activity, expressed as IC50 values, was determined using the MTT assay. CPT-11 was significantly more active in SCLC than in NSCLC cell lines (P = 0.0036), whereas no significant difference between histological types was observed with SN-38. A significant correlation (r2 = 0.52, P = 0.028) was observed between CE activity and chemosensitivity to CPT-11 but not to SN-38, and significantly higher CE activity was observed in SCLC compared with NSCLC cell lines (P = 0.025). Western blotting experiments showed topoisomerase I protein expressions within a factor of 2, and a granular nuclear staining was detectable in all cell lines by immunocytochemistry of cytospins. No correlation was observed between protein expression and sensitivity to CPT-11 or SN-38. Cellular and medium concentrations of CPT-11 and SN-38 were measured by high-performance liquid chromatography (HPLC) in one SCLC cell line with high CE activity and high sensitivity to CPT-11, and one NSCLC cell line with low sensitivity to CPT-11 and CE activity. Intracellular concentrations of CPT-11 and SN-38 were higher in the SCLC cell line, and this was associated with an increase in cellular uptake of CPT-11 compared with the medium, and an increased intracellular formation of SN-38. In conclusion, CE activity appears to be associated with higher sensitivity to CPT-11 in human lung cancer cell lines and may partly explain the difference in the in vitro sensitivity to CPT-11 between SCLC and NSCLC cells. The assessment of CE activity in clinical material of lung cancer patients undergoing treatment with CPT-11 may be warranted. However, other mechanisms may influence sensitivity to CPT-11, possibly including drug transport.
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PMID:Determinants of CPT-11 and SN-38 activities in human lung cancer cells. 964 29

Irinotecan is a new topoisomerase I inhibitor. It has demonstrated antitumor activity in solid tumors, independently of the histologic type, and in squamous cervical carcinoma. Its original mechanism of action offers the possibility to combine it with other drugs. In vitro and in vivo studies have demonstrated synergistic activity between irinotecan, cisplatin and etoposide. This article reviews the main published phases I and II studies with irinotecan. The limiting toxicity of combination schedules in neutropenia. The best results were obtained with the association cisplatin-irinotecan in lung cancer. For the combination etoposide-irinotecan the best schedule of administration remains to be determined.
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PMID:[Irinotecan-containing combinations in solid tumors, except colonic carcinomas]. 993 85

A study was undertaken to determine the maximum tolerated dose, the dose-limiting toxicities, and the response rate of irinotecan administered weekly with concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer. In a phase I/II clinical trial, patients with histologically documented, surgically unresectable stage IIIA or IIIB non-small cell lung cancer (NSCLC) were enrolled. Irinotecan was administered as a 90 min intravenous infusion once weekly for 6 weeks. The starting dose was 30 mg m(-2) and dose escalation was done in 15 mg m(-2) increments. Dose-limiting toxicity was defined as grade 3 nonhaematologic toxicity (excluding nausea, vomiting and alopecia) or grade 4 haematologic toxicity according to the WHO criteria. Radiation was delivered to the primary tumour and regional lymph nodes (40 Gy), followed by a boost to the primary tumour (20 Gy). Twenty-seven patients were entered into this study at three irinotecan dose levels (30, 45 and 60 mg m(-2)). Twenty-six eligible patients were evaluated for toxic effects and clinical outcome. Severe oesophagitis, pneumonitis, and diarrhoea occurred at 45 and 60 mg m(-2). Three of the five patients given 60 mg m(-2) developed grade 3 or 4 oesophagitis and pneumonitis. In addition, one patient died of pneumonitis after completing therapy at 45 mg m(-2) in the phase II study. The objective response rate was 76.9% (95% CI, 53.0-88.9%). Oesophagitis, pneumonitis, and diarrhoea are the dose-limiting toxicities of weekly irinotecan combined with thoracic irradiation. The maximum tolerated dose and the dose for the phase II study were 60 and 45 mg m(-2) wk(-1), respectively. This combined therapy for locally advanced non-small cell lung cancer is promising and shows acceptable toxicity.
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PMID:Phase I/II study of weekly irinotecan and concurrent radiation therapy for locally advanced non-small cell lung cancer. 1018 91

This review summarizes the results reported in preclinical and clinical trials of three novel anticancer drugs developed and tested in Japan. In phase II trials, Irinotecan, a semisynthetic analog of camptothecin, has yielded response rates exceeding 20% in non-small-cell lung cancer, small-cell lung cancer, breast cancer, gastric cancer, colorectal cancer, ovarian cancer, uterine cervical cancer, and non-Hodgkini's lymphoma. It was modestly active on pancreatic cancer and was not active on acute leukemias. Dose-limiting toxicities were leukopenia and diarrhea, and other major toxicities were nausea, vomiting, and alopecia. Amrubicin, a totally synthetic anthracycline, exhibited both higher efficacy on human tumor xenografts and cardiotoxicity milder than that of doxorubicin in preclinical studies. The dose-limiting toxicity in phase I trials was leukopenia. In phase II trials, amrubicin has shown activity equivalent to that of doxorubicin on non-Hodgkin's lymphoma, response rates exceeding 20% on non-small-cell lung cancer, and a response rate of 78.8% on untreated extensive-stage small-cell lung cancer. S-1 is an oral formulation consisting of ftorafur (an analog of 5-fluorouracil), 5-chloro-2, 4-dehydropyrimidine, which inhibits degradation of 5-fluorouracil, and potassium oxonate, which reduces gastrointestinal toxicity, at a molar ratio of 1:0.4:1. In phase I trials, dose-limiting toxicities (myelosuppression and gastrointestinal toxicities) were judged to be milder than those induced by UFT (ftorafur plus uracil). The response rates obtained in phase II trials were 40-49% on advanced gastric cancer, 35.5% on colorectal cancer, 37.5% on head and neck cancer, and 40.7% on breast cancer.
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PMID:Novel anticancer drugs in Japan. 1023 66

Given that human cancer xenografts tend to retain chemosensitivities similar to the cancerous tissue of origin, human carcinoma xenografts grown in nude mice were tested for sensitivity to four drug protocols: doxorubicin at 5 mg/kg, i.v., q5d; irinotecan at 60 mg/kg, i.v., q4d; cisplatin 5 mg/kg, i.p., q7d; and topotecan 1.5 mg/kg, p.o., qd (5 of 7 days). Irinotecan and doxorubicin protocols either halted or caused significant regression of the breast cancer cell lines (MCF7, MDA-MB 231 and T47D). None of the protocols tested resulted in significant regression in the lung cancer xenografts (H460, A549 and H226) although both irinotecan and doxorubicin did halt growth of the H226 xenograft. The ability of the irinotecan treatment to cause regression of xenograft size in all three colon cancer cell lines (SW620, COLO205 and HT29) justifies further clinical trials of irinotecan as an especially promising drug for the treatment of colon cancer.
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PMID:Efficacy of treatment of colon, lung and breast human carcinoma xenografts with: doxorubicin, cisplatin, irinotecan or topotecan. 1047 42


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