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)

Survival in lung cancer patients has not improved over the past 2 decades. Irinotecan (Camptosar, CPT-11), a semisynthetic analog of the quinoline-based alkaloid camptothecin, is one of several new drugs that have demonstrated promising activity in the treatment of lung cancer in recent years. This article gives a brief overview of the mechanism, development history, and current uses of this agent.
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PMID:Current status of irinotecan in lung cancer. 1122 Oct 22

Chemotherapy is currently the main treatment for all stages of small-cell lung cancer. In extensive disease, etoposide/cisplatin (Platinol) is standard treatment, and in limited disease, etoposide/cisplatin with early concurrent thoracic radiotherapy twice daily is a typical regimen. Therapeutic outcomes, however, leave substantial room for improvement. The topoisomerase I inhibitor irinotecan (Camptosar, CPT-11) is one of the most active agents against small-cell lung cancer. In a phase II study, irinotecan yielded response rates of 33% to 50%, depending on prior treatment status. Combinations with cisplatin have resulted in a median survival of 14.3 months in patients with limited disease and 13.0 months in extensive disease. A phase III study in extensive-disease small-cell lung cancer compared irinotecan/cisplatin and standard etoposide/cisplatin regimens, and demonstrated a significant difference in survival in the irinotecan-containing arm (411 vs 282 days). Planned phase III studies in North America will confirm and extend these results. Based on these promising data, irinotecan/cisplatin regimens represent a new standard treatment for extensive-disease small-cell lung cancer.
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PMID:New state of the art in small-cell lung cancer. 1122 Oct 23

We examined the effect of berberine, a major component with anti-fungal properties contained in Coptidis Rhizoma and Phellodendri Cortex, on the lymph node metastasis of murine lung cancer. Oral administration of berberine for 14 days significantly inhibited the spontaneous mediastinal lymph node metastasis produced by orthotopic implantation of Lewis lung carcinoma (LLC) into the lung parenchyma in a dose-dependent manner, but did not affect the tumor growth at the implantation site of the lung. Combined treatment with berberine and an anti-cancer drug, CPT-11, resulted in a marked inhibition of tumor growth at the implantation site and of lymphatic metastasis, as compared with either treatment alone. Anti-activator protein-1 (anti-AP-1) transcriptional activity of non-cytotoxic concentrations of berberine caused the inhibition of the invasiveness of LLC cells through the repression of expression of urokinase-type plasminogen activator (u-PA).
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PMID:Inhibitory effect of berberine on the mediastinal lymph node metastasis produced by orthotopic implantation of Lewis lung carcinoma. 1124 16

It has been reported that 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), have absorption characteristics of weakly basic drugs, suggesting that alkalization of the intestinal lumen might reduce reabsorption and its attendant side effects. Furthermore, stasis of stools containing these compounds is thought to induce damage to the intestinal mucosa. The prevention of CPT-11-induced side effects by oral alkalization (OA) combined with control of defecation (CD) was estimated in a case-control study of lung cancer patients. Coinciding with day 1 of CPT-11 infusion and for 4 days thereafter, OA and CD were practiced utilizing orally administered sodium bicarbonate, magnesium oxide, basic water and ursodeoxycholic acid. OA involved the daily use of all four therapeutics, and CD required doses of up to 4.0 g/day of magnesium oxide and 2 L/day of excess basic water. From three ongoing prospective phase I/II studies, we selected 37 consecutive patients who were treated with CPT-11 in combination with cisplatin in the presence of OA and CD (group B). Thirty-two control subjects who were matched to the background characteristics of the case patients were treated with the same regimen in the absence of OA and CD (group A). Toxicities induced by the CPT-11/cisplatin combination were evaluated and analyzed in group A and group B in a case-control format. The use of OA and CD resulted in significantly higher stool pH (p < 0.0001), while reducing the incidence of delayed diarrhea (> or = grade 2: group A 32.3% versus group B 9.4%; p = 0.005), nausea (p = 0.0001), vomiting (p = 0.001) and myelotoxicity, especially granulocytopenia (p = 0.03) and lymphocytopenia (p = 0.034). In addition, dose intensification was well tolerated in patients receiving OA and CD, allowing dose escalation from 35.6 +/- 6.0 to 39.9 +/- 5.6 mg/m(2)/week (p < 0.001). Tumor response rates for non-small cell lung cancer were 59.3% (16/27 patients) in group B compared with 38.5% (10/26 patients) in group A. Multivariate analysis revealed that the risk of CPT-11-induced delayed diarrhea greater than grade 2 was associated with OA and CD (odds ratio for delayed diarrhea, 0.14 with use of OA and CD; 95% confidence interval, 0.05 to 0.4; p = 0.0002) and age (odds ratio, 1.08 per increase in age; 95% confidence interval, 1.02 to 1.15; p = 0.009). OA and CD appear to be useful in preventing the dose-limiting side effects of CPT-11 noted in clinical practice, mainly nausea, vomiting, granulocytopenia and especially delayed diarrhea. Risk factors statistically associated with delayed diarrhea include advanced age and the use of CPT-11 without OA and CD.
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PMID:Prevention of irinotecan (CPT-11)-induced diarrhea by oral alkalization combined with control of defecation in cancer patients. 1129 Oct 56

Gemcitabine (Gemzar) and irinotecan (CPT-11, Camptosar) are active cytotoxic drugs against pancreatic cancer. Preclinical data evaluating the combination of gemcitabine and irinotecan suggest dose-dependent synergistic interactions in SCOG small-cell lung cancer and MCF-7 breast cancer cell lines. Two phase I trials of this combination have been reported to date: the day 1 and 8 every-3-week schedule (IrinoGem trial), and the day 1, 8, and 15 every-4-week schedule (MSKCC trial). Both trials aimed to determine the maximum tolerated dose of irinotecan when administered as a 90-minute i.v. infusion either immediately after (IrinoGem) or before or immediately after (MSKCC) gemcitabine at 1,000 mg/m2 by 30-minute i.v. infusion in patients with solid tumors. The achieved maximum tolerated dose of IrinoGem has a higher dose intensity of irinotecan (100 mg/m2 on days 1 and 8, every-3-week cycle) compared with the MSKCC schedule (60 mg/m2 on days 1, 8, and 15, every-4-week trial). In IrinoGem, two of three previously untreated metastatic pancreas cancer patients had durable radiologic partial responses. The third had stable disease with clinical benefit for eight cycles. In addition, a patient with metastatic adenocarcinoma of unknown primary--potentially pancreatic--has had a durable response and is alive more than 30 months after the diagnosis. Preliminary results of a 45-patient multicenter phase II trial with IrinoGem in advanced and metastatic pancreas cancer were recently reported. Toxicity was modest, with no toxic deaths or neutropenic fever. Radiologic response rate was 20% of patients (9 out of 45), and a CA 19-9 decrease of more than 50% from baseline values occurred in 32.5% of patients (13 out of 40). Median survival was 6 months (range: 0.9 to 12.2+ months) and median time to treatment failure was 2.9 months (range: 0.1 to 11.3+ months). A pivotal international multicenter phase III trial comparing IrinoGem to single-agent gemcitabine in advanced and metastatic pancreas cancer is ongoing.
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PMID:Irinotecan/gemcitabine combination chemotherapy in pancreatic cancer. 1130 41

Current agents for the treatment of non-small-cell lung cancer include gemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere), vinorelbine (Navelbine), and irinotecan (CPT-11, Camptosar). Experimental agents include pemetrexed (LY231514, Alimta) and tirapazamine. Molecular and biological therapies include angiogenesis inhibitors, epidermal growth factor receptor inhibitors, HER2/neu inhibitors, and inhibitors of ras activation and function. Doublet chemotherapy is currently the standard treatment for advanced non-small-cell lung cancer. In the past 2 years, randomized trials have shown that many of the new two-drug combinations used to treat non-small-cell lung cancer have equivalent efficacy. These combinations produce 1-year survival rates of about 35% and 2-year survival rates of about 15%. Toxicity rates vary but are sufficiently low as to make the development of three-drug combinations feasible. Preliminary studies from several phase I and II trials suggest that triplet therapy can improve survival beyond that of double therapy regimens.
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PMID:Triplet combination chemotherapy and targeted therapy regimens. 1130 45

A phase II study of fractionated administration of irinotecan (CPT-11) and cisplatin (CDDP) in patients with non-small-cell lung cancer (NSCLC) was conducted. Between January 1996 and January 1998, 44 previously untreated patients with stage IIIB or IV NSCLC were enrolled. CDDP at a dose of 60 mg x m(-2) was given first and followed by CPT-11 at a dose of 50 mg x m(-2). Both drugs were given by 1-hour infusion on days 1 and 8, and repeated every 4 weeks up to 4 cycles. 42 patients were evaluated for response and 44 for survival and toxicity. 20 patients (48%: 95% confidence interval 32-63%) achieved an objective response. The median duration of responses was 8 months, and the median survival time and the 1-year survival rate were 12.5 months and 56.8%, respectively. Major toxicities were neutropenia and diarrhoea. Grade 3 or 4 neutropenia occurred in 70.5% of the patients and one patient died of sepsis. Grade 3 or 4 diarrhoea was experienced in 25.0%, but manageable by conventional therapy. In conclusion, fractionated administration of CPT-11 and CDDP was highly effective for advanced NSCLC with manageable toxicities.
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PMID:Fractionated administration of irinotecan and cisplatin for treatment of non-small-cell lung cancer: a phase II study of Okayama Lung Cancer Study Group. 1143 95

Irinotecan (CPT-11, Camptosar) is a camptothecin derivative that is thought to exert its cytotoxic effects by targeting topoisomerase I. It is believed that irinotecan stabilizes a DNA-topoisomerase I cleavable complex, and that interactions between this complex and the replication machinery may lead to cell death. There is a significant volume of in vitro and in vivo data demonstrating that irinotecan acts as a radiosensitizer. The exact mechanism of this radiosensitization is currently unknown. The increasing amount of data demonstrating improved outcomes with concurrent chemoradiation treatment of malignancies like lung cancer and head and neck cancer provide impetus for pursuing the addition of other drugs as radiosensitizers to improve local control further. Irinotecan is undergoing early clinical trials in the combined-modality setting in several disease sites. This article will provide an overview of the current status of irinotecan used concurrently with radiotherapy in the treatment of a variety of solid tumors.
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PMID:Irinotecan and radiation in combined-modality therapy for solid tumors. 1149 28

Irinotecan (CPT-11, Camptosar), either alone or in combination with cisplatin (Platinol), has demonstrated activity in advanced non-small-cell lung cancer (NSCLC). In single-agent studies, response rates as high as 35% have been observed; in combination with cisplatin, response rates have ranged as high as 50%, with 1-year survival rates of 33% to 58%. A critical phase III randomized trial comparing irinotecan, either alone or in combination with cisplatin, to vindesine/cisplatin, demonstrated superior survival for stage IV patients receiving irinotecan. The first North American effort to replicate the schedule used in the phase III trial (cisplatin 80 mg/m2 and irinotecan 60 mg/m2 on days 1, 8, and 15 every month) yielded a response rate of 29%, median survival time of nearly 10 months, and 1-year survival rate of 37%. A subsequent multi-institutional trial conducted through Vanderbilt Cancer Center Affiliate Network and Fox Chase Cancer Center combined both agents on a weekly schedule in an attempt to exploit their putative synergy and to potentially decrease toxicity. This schedule, which employed irinotecan 65 mg/m2 and cisplatin 30 mg/m2 both weekly x 4, was better tolerated than the monthly cisplatin combination with a higher response rate (36%), median survival (11.6 months), and 1-year survival rate (46%). Multiple phase I and phase II studies have combined irinotecan with taxanes, either alone or in concert with carboplatin (Paraplatin), yielding similar response and survival rates. Finally, a critical phase III trial from Japan has demonstrated superior outcome for irinotecan and cisplatin vs standard etoposide/cisplatin in the treatment of extensive small-cell carcinoma of the lung. At least one North American trial will determine if these results are reproducible.
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PMID:The emerging world role of irinotecan in lung cancer. 1149 27

During the past decade, five new cytotoxic drugs have been introduced that are active against non-small-cell lung cancer (NSCLC). These agents include vinorelbine (Navelbine), paclitaxel (Taxol), docetaxel (Taxotere), gemcitabine (Gemzar), and irinotecan (CPT-11, Camptosar). Used alone, these drugs display activity comparable to cisplatin. The combination of cisplatin and one of the newer drugs produces better survival than treatment with cisplatin (Platinol) alone. Randomized studies of chemotherapy regimens that include these newer drugs have demonstrated improved survival, fewer side effects, or both, compared with earlier standard combinations such as cisplatin/vindesine or cisplatin/etoposide. Docetaxel and perhaps some of the other newer drugs are of value for patients previously treated with platinum-containing regimens. Future studies should determine whether combinations of these newer drugs are superior to cisplatin-containing regimens. Although improved survival is the most important factor in defining the best regimen in non-small-cell lung cancer, additional considerations include patient tolerability, costs of administration, and the rationale for and ability to include noncytotoxic agents (such as inhibitors of signal transduction pathwriys or angiogenesis) into the therapeutic program.
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PMID:Rationale for non-platinum chemotherapy in advanced NSCLC. 1149 29


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