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)

This multicenter study enrolled 73 patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). The study design was based on the hypothesis that the non-overlapping toxicities of a 3-drug combination of irinotecan (Camptosar, CPT-11), carboplatin (Paraplatin), and paclitaxel (Taxol) would allow them to be dosed at recommended or standard doses, respectively. Of the 32 patients in phase I portion of the trial, six received irinotecan 40 mg/m2 plus carboplatin at an area-under-curve (AUC) of 6 and paclitaxel 225 mg/m2 on an every-3-week schedule (regimen A). Due to the unexpectedly severe toxicity associated with this regimen, the carboplatin and paclitaxel doses were reduced, while the irinotecan doses were escalated from 40 to 80 to 125 mg and reduced to 100 mg/m2 (regimen B). In the phase II portion of the trial, irinotecan was dosed at 100 mg/m2 because 3 of 8 patients who received the 125 mg/m2 dose in phase I experienced first-course grade 3/4 toxicities. However, the toxicity of regimen B proved unacceptably severe in phase II; 13 of the 40 patients (35%) experienced grade 3/4 neutropenia and 30% suffered febrile or septic neutropenia. The unconfirmed objective response rate in phase I was 64.5%; median time to progression and median survival were 7.1 months and 11.6 months, respectively, and 1-year survival was 46.9%. The unconfirmed objective response rate in phase II was 60.6%, including one complete response (CR) and 19 partial responses (PRs); one CR and 16 PRs were subsequently confirmed. The efficacy and toxicity of this triple combination strongly suggest significant pharmacokinetic and/or pharmacodynamic interactions, warranting continued clinical investigation.
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PMID:Phase I/II trial of irinotecan, carboplatin, and paclitaxel in advanced or metastatic NSCLC. 1098 Dec 88

In preclinical studies, the topoisomerase I inhibitor irinotecan (Camptosar, CPT-11) has demonstrated activity as a radiosensitizer, probably due to its ability to inhibit potentially lethal radiation damage repair. We conducted a phase I trial to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of weekly irinotecan with concurrent thoracic radiation therapy for patients with unresectable stage III non-small-cell lung cancer. For this study, 13 patients received three dose escalations (from 30 to 40 to 50 mg/m2/wk). At the first dose level, one patient developed grade 5 esophagitis. Accrual was expanded to seven patients. None of the remaining six patients developed esophagitis. At the second dose level (40 mg/m2/wk), the worst toxicity, which developed in one patient, was grade 2 esophagitis. At the third dose level (50 mg/m2/wk), two of three patients developed grade 4 nausea and vomiting; grade 3 or 4 esophagitis also occurred in two patients. Of the 12 evaluable patients, seven achieved a partial response, for an overall response rate of 58%. In conclusion, nausea, vomiting, and esophagitis appear to be the principal DLTs of concurrent weekly irinotecan and thoracic radiation in the outpatient setting. The MTD of concurrent weekly irinotecan with thoracic radiation therapy appears to be 40 mg/m2 weekly for 6 weeks. To confirm the MTD of this combination, this study is still open to accrual at the second dose level (40 mg/m2) in combination with carboplatin.
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PMID:Weekly irinotecan and concurrent radiation therapy for stage III unresectable NSCLC. 1098 Dec 90

This phase I/II nonrandomized, open-label study was designed to assess the safety and benefit of sequencing irinotecan (Camptosar, CPT-11) plus paclitaxel (Taxol) immediately after cisplatin (Platinol)/etoposide (VePesid, VP-16) or carboplatin (Paraplatin)/etoposide in patients with extensive small-cell lung cancer (SCLC). Ten patients were evaluable in phase I; all had previously been treated with cisplatin and etoposide, and five of the 10 had also previously received carboplatin and paclitaxel. All 10 patients were given a fixed dose of irinotecan (60 mg/m2) and escalating doses of paclitaxel weekly for 3 weeks. Three patients had grade 4 toxicities, one at the lowest dose level of paclitaxel (15 mg/m2). Two patients had grade 3 toxicities. The dose-limiting toxicity occurred at the 60 mg/m2 paclitaxel dose level, when the performance status of both patients in that group decreased to 60 (Karnofsky scale). Two patients had progressive disease after 1 month of treatment and did not receive cycle 2. Three of seven patients evaluable for response had complete remissions. A fourth patient had resolution of lymphangitic metastases and resolution of a partial small bowel obstruction but did not have measurable disease. The fifth patient had a partial remission. The ongoing phase II portion of the study is restricted to previously untreated patients who will receive at least one cycle of either cisplatin or carboplatin in combination with etoposide followed by irinotecan at 60 mg/m2 and paclitaxel at 50 mg/m2 dosed once weekly for 3 weeks.
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PMID:Phase I/II study of weekly irinotecan and paclitaxel in patients with SCLC. 1098 Dec 93

Gemcitabine (2'-2'-difluorodeoxycytidine; dFdC) is a deoxycytidine analogue which is effective against solid tumours, including lung cancer and ovarian cancer. dFdC requires phosphorylation by deoxycytidine kinase (dCK) for activation. In the human ovarian cancer cell line A2780 and its 30,000-fold dFdC-resistant variant AG6000 (P<0.001), we investigated the cross-resistance profile to several drugs. AG6000, which has a complete dCK deficiency, was approximately 1000-10,000-fold resistant to other deoxynucleoside analogues such as 1-beta-D-arabinofuranosyl cytosine, 2-chloro-deoxyadenosine, aza-deoxycytidine and 2', 2'-difluorodeoxyguanosine (dFdG) (P<0.001). dFdG can be activated by dCK and deoxyguanosine kinase (dGK), but the latter enzyme was not altered in AG6000 cells. Thus dFdG resistance was only due to dCK deficiency. AG6000 was 1.6- and 46.7-fold resistant to 5-fluorouracil (5-FU) and ZD1694, respectively (the latter was significant; P<0.01), which may be due to the 1.7-fold higher thymidylate synthase (TS) activity, but AG6000 cells were also 2. 7-fold resistant to the lipophilic TS inhibitor AG337 (P<0.05). Remarkably, AG6000 cells were 2.5-fold more sensitive to methotrexate (MTX) (P<0.01) than A2780 cells, but 1.6-fold more resistant to trimetrexate (TMQ) (P<0.10). However, no differences in reduced folate carrier activity, folylpolyglutamate synthetase (FPGS) activity and polyglutamation of MTX were found between the cell lines. AG6000 cells were approximately 2 to 7.5-fold more resistant to doxorubicin (DOX), daunorubicin (DAU), epirubicin and vincristine (VCR) (the latter was significant; P<0.02) and approximately 4-fold more resistant to the microtubule inhibitors paclitaxel and docetaxel (P<0.001). Fluorescent activated cell sorter (FACS) analysis revealed no P-glycoprotein (Pgp) or multidrug resistance-associated protein (MRP) expression, but less fluorescence of intercalated DAU in AG6000 cells. An approximately 2-fold resistance to the topoisomerase I and II inhibitors etoposide, CPT-11 and SN38 was found in AG6000 cells. Topoisomerase I and IIalpha RNA expression was decreased in AG6000 cells. AG6000 was 2.4, 2.4, 2.3 and 3.7-fold more resistant to EO9 (P<0.02), mitomycin-C (MMC) (P<0.05), cisplatin (CDDP) (P<0.10) and maphosphamide (MAPH), respectively. DT-diaphorase (DTD), which activates EO9, was 2.2-fold lower in AG6000 cells. CDDP resistance might be related to a reduced retention of DNA adducts in AG6000. However, glutathione levels were equal in A2780 and AG6000 cells. A 24 h exposure to DOX, VCR and paclitaxel at equimolar and equitoxic concentrations, resulted in more double-strand breaks (1.5- to 2-fold) in A2780 than in AG6000 cells. MAPH at 1120 nM and 17 nM of EO9 did not cause DNA damage in either cell line. In conclusion, AG6000 is a cell line highly cross-resistant to a wide variety of drugs. This cross-resistance might be related to altered enzyme activities and/or increased DNA repair.
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PMID:Cross-resistance in the 2',2'-difluorodeoxycytidine (gemcitabine)-resistant human ovarian cancer cell line AG6000 to standard and investigational drugs. 1100 May 80

Among the numerous clinical regimens used in combination chemotherapy, synergy is particularly marked in combinations containing cisplatin (CDDP). However, the clinical use of CDDP is sometimes limited due to its nephrotoxicity. Nedaplatin (NDP) is a second-generation platinum complex with reduced nephrotoxicity that may substitute for CDDP or even surpass it for use in combination with other drugs. We investigated the effects of combinations of NDP and other anticancer drugs on the growth of human small cell lung cancer cells (SBC-3) and non-small cell lung cancer cells (PC-14) using a three-dimensional analysis model. Among the combinations tested, the combination of NDP and irinotecan (CPT-11) showed the most marked synergistic interaction, and the synergism has also been observed against PC-14 cells. With regard to treatment schedule, a remarkable synergistic interaction was produced by concurrent exposure to NDP and CPT-11. On the other hand, sequential exposure to the two drugs led only to additivity. To analyze the interaction between the drugs, the effect of NDP on the 7-ethyl-1-hydroxy-CPT (the active form of CPT-11)-induced inhibitory effect on DNA topoisomerase I was examined. The topoisomerase I-inhibitory effect of 7-ethyl-1-hydroxy-CPT was enhanced 10-fold in the presence of NDP at microgram/milliliter concentrations. These biochemical interactions might be responsible for the synergistic interaction between NDP and CPT-11. These results suggest that the combination of NDP with CPT-11 may be clinically useful for the chemotherapy of lung cancer.
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PMID:In vitro synergistic interactions between the cisplatin analogue nedaplatin and the DNA topoisomerase I inhibitor irinotecan and the mechanism of this interaction. 1120 10

There will be approximately 40,000 new cases of small-cell lung cancer this year. Prior to 1990, there were several agents with single-agent response rates of 30% to nearly 90% in the untreated small-cell lung cancer population and approximately 10% to 20% in relapsed patients. During the 1990s, several new chemotherapy agents have displayed activity in small-cell lung cancer (paclitaxel [Taxol], gemcitabine [Gemzar], vinorelbine [Navelbine], topotecan [Hycamtin], and irinotecan [Camptosar, CPT-11]). The majority of studies with irinotecan have been conducted in Japan. The US experience is limited to a single multi-institution trial that was conducted in patients with previously treated small-cell lung cancer. A total of 44 patients were entered in the study. Patients were stratified by response to prior therapy. Responses occurred in 7 of 44 patients for an overall response rate of 14%. The overall median survival was 4.8 months.
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PMID:Irinotecan in small-cell lung cancer: the US experience. 1122 Oct 15

Preclinical data suggest that irinotecan (Camptosar, CPT-11), a novel topoisomerase I inhibitor, has exhibited promising activity in the treatment of lung cancer. In a phase II study of non-small-cell lung cancer, irinotecan demonstrated a 32% response rate. Combinations of irinotecan and cisplatin (Platinol) have also demonstrated synergistic activity against non-small-cell lung cancer. A phase I trial of irinotecan combined with cisplatin in previously untreated non-small-cell lung cancer patients showed an encouraging response rate of 54%, with irinotecan at 60 mg/m2 on days 1, 8, and 15, plus cisplatin at 80 mg/m2. In a phase II study of chemotherapy-naive patients with stage IIIB/IV non-small-cell lung cancer, irinotecan/cisplatin yielded a response rate of 52% and a mean survival time of 44 weeks. Data from a phase III trial comparing cisplatin at 80 mg/m2 on day 1 plus vindesine at 3 mg/m2 on days 1, 8, and 15 with two irinotecan-containing regimens--cisplatin at 80 mg/m2 on day 1 plus irinotecan at 60 mg/m2 on days 1, 8, and 15, and single-agent irinotecan at 100 mg/m2 on days 1, 8, and 15--have also been reported. Responses were observed in 32%, 44%, and 21% of patients for the vindesine/cisplatin, irinotecan/cisplatin, and irinotecan arms, respectively, with corresponding median survival times of 45.6, 50.0, and 46.0 weeks; there were no significant differences in response rate or survival between treatment groups for all patients. However, subset analysis of stage IV patients indicated a significant survival advantage for irinotecan/cisplatin; the median survival time was 50 weeks for patients receiving irinotecan/cisplatin, 36.4 weeks for vindesine/cisplatin, and 42.1 weeks for irinotecan (P = .004 for the irinotecan/cisplatin arm vs vindesine/cisplatin; P = .018 for irinotecan vs vindesine/cisplatin). Another phase III study compared irinotecan/cisplatin and vindesine/cisplatin. There was no difference in overall median survival time, and the median survival times were not significantly different for stage IV patients in the respective irinotecan/cisplatin and vindesine/cisplatin arms (44.7 vs 45.3 weeks). Further studies are needed to determine whether irinotecan/cisplatin combinations improve survival in comparison with other promising platinum-containing regimens.
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PMID:Establishment of the standard regimen for non-small-cell lung cancer in Japan. 1122 Oct 16

Topoisomerase I inhibitors have demonstrated significant activity in non-small-cell lung cancer. In phase II studies, particularly in Japan, single-agent irinotecan (Camptosar, CPT-11) has produced response rates as high as 35%. In combinations with cisplatin (Platinol), it has also resulted in overall response rates of 41% to 52%, with median survival of 10.2 to 13 months, and 1-year survival rates of 33% and 58%. A Japanese phase III randomized trial of irinotecan, either alone or in combination with cisplatin vs vindesine/cisplatin in previously untreated stage IIIB/IV non-small-cell lung cancer, demonstrated that survival among stage IV patients was significantly better in the irinotecan arms compared to the vindesine/cisplatin group. However, another Japanese phase III study comparing irinotecan/cisplatin to vindesine/cisplatin failed to show a survival difference. Initial North American efforts recapitulated this work, while a follow-up study incorporated weekly irinotecan with weekly cisplatin, yielding a response rate of 36%, median survival of 11.6 months, and a 1-year survival rate of 46%. Irinotecan/taxane combinations have also shown promise. Phase I/II studies in advanced non-small-cell lung cancer with paclitaxel (Taxol), irinotecan, and carboplatin (Paraplatin) produced a response rate of 38%, median survival of 11 months, and a 1-year survival rate of 47%; other trials with irinotecan and paclitaxel are ongoing. Phase I data for irinotecan/docetaxel (Taxotere) have indicated an overall response rate of 32%, median survival of 39 weeks, and a 1-year survival rate of 38%; subsequent phase II trials used either cisplatin or irinotecan in combination with docetaxel and yielded a promising median survival of 45.6 weeks, comparable to the standard cisplatin/docetaxel combination. Phase I trials with irinotecan and gemcitabine (Gemzar) have also yielded promising results. Follow-up efforts include phase II studies in both chemonaive advanced non-small-cell lung cancer and progressive small-cell lung cancer (salvage therapy). Clearly, clinical trial data have demonstrated the utility of irinotecan in the treatment of advanced non-small-cell lung cancer. Planned combinations with new chemotherapeutic agents and biological response modifiers may provide additional treatment options.
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PMID:Treatment of non-small-cell lung cancer in North America: the emerging role of irinotecan. 1122 Oct 17

Cisplatin (Platinol)-based chemotherapy has been the standard systemic therapy for both non-small-cell and small-cell lung cancer for the past 2 decades, though the efficacy and benefit remain modest. Recently, several novel agents have been introduced that have single-agent activity comparable to cisplatin and offer the possibility of improved therapy for lung cancer. Camptothecin and taxane derivatives are associated with both different mechanisms of action and nonhematologic toxicities, and have demonstrated additive or synergistic activity when used in combination in preclinical studies. We review pertinent clinical studies of these agents in lung cancer and present our experience in combining irinotecan (Camptosar, CPT-11) with taxanes on a weekly schedule in dose-finding and efficacy studies. When chemotherapy is delivered for 4 consecutive weeks followed by a 2-week rest, hematologic toxicity is dose limiting and most prominent during weeks 3 and 4. Dose intensification is feasible if the schedule is modified so the chemotherapy is given on days 1 and 8, with cycles repeated every 3 weeks. The most common nonhematologic toxicities remain asthenia, neuropathy, and diarrhea. Future studies will explore and better define the role of these drug combinations in the treatment of lung cancer.
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PMID:Rationale and dose-finding studies of the combination of irinotecan and a taxane on a weekly schedule. 1122 Oct 18

The management of non-small-cell lung cancer is undergoing rapid evolution. Although the advent of combined-modality therapy has led to improved survival, most patients eventually succumb to the disease. The arrival of a new generation of chemotherapeutic agents--including the taxanes, gemcitabine (Gemzar), and topoisomerase inhibitors such as irinotecan (Camptosar, CPT-11)--offers the hope of advances against this malignancy. Irinotecan, a camptothecin derivative, has shown impressive activity in a variety of solid tumors, including non-small-cell lung cancer. It is believed to act by stabilizing the topoisomerase-DNA complex formed during diverse cellular processes, including replication and transcription. A considerable body of evidence also demonstrates that camptothecin and its derivatives possess substantial radiosensitization properties. This article will review the in vitro and in vivo data on irinotecan's ability to render tumors more susceptible to ionizing radiation. It will then focus on experience with irinotecan and thoracic radiation in the treatment of non-small-cell lung cancer, which has yielded acceptable toxicity results and response rates in excess of 60% in early trials. It is hoped that newer treatment strategies--such as the combination of radiation and irinotecan in lung cancer--will significantly impact cure rates in the future.
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PMID:Irinotecan in combined-modality therapy for locally advanced non-small-cell lung cancer. 1122 Oct 19


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