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)

We recently reported that acidic (aFGF) and basic (bFGF) fibroblast growth factors confer a broad spectrum chemoresistance in solid tumors, and that suramin, an inhibitor of multiple growth factors including aFGF and bFGF, enhanced the in vitro antitumor activity of several anticancer drugs including paclitaxel (Song, S., et al., Proc. Natl. Acad. Sci. USA, 97: 8658-8663, 2000). The present study investigated in vitro and in vivo interaction between paclitaxel and suramin, using human PC3-LN cells which, upon i.v. injection into immunodeficient mice, yielded lung metastases in 100% of animals. In in vitro studies, conditioned medium (CM) obtained from histocultures of rat lung metastases induced a 3-fold resistance. The addition of suramin had no effect in the absence of CM but reversed the CM-induced resistance; calculations based on the IC(50) values indicate a complete reversal in the presence of <20 microM suramin. Analysis by the combination index method indicates a synergistic interaction between paclitaxel and suramin. In in vivo studies, animals with well-established lung metastases (at least five nodules of 1 mm in diameter) were treated i.v. with paclitaxel (15 mg/kg) and suramin (10 mg/kg) administered twice weekly for 3 weeks. Single-drug therapy with paclitaxel or suramin did not reduce body weight. Suramin alone had no antitumor activity. Paclitaxel alone reduced the tumor size by approximately 75%, reduced the density of nonapoptotic cells by approximately 70% in residual tumors, and enhanced the fraction of apoptotic cells by approximately 3-fold. The addition of suramin to paclitaxel therapy enhanced the antitumor effect, resulting in an additional 5-fold reduction of tumor size, an additional 9-fold reduction of the density of nonapoptotic cells, and an additional 30% increase in the apoptotic cell fraction. These data indicate significant enhancement of the efficacy of paclitaxel by suramin and support the use of nontoxic doses of suramin with paclitaxel in the treatment of lung cancer.
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PMID:Nontoxic doses of suramin enhance activity of paclitaxel against lung metastases. 1150 65

Non-small cell lung cancer (NSCLC) is a systemic illness. The majority of newly diagnosed patients depend on systemic chemotherapy to improve outcome. Among the new chemotherapeutic agents recently tested, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has shown convincing single-agent activity in advanced NSCLC. The two initial phase II studies using paclitaxel alone showed a 1-year survival rate of 40%, comparable to that seen with combination regimens. Paclitaxel/carboplatin is one of several standard regimens for patients with stage IIIB to IV disease. It is as effective as any other new agent/platinum combination studied to date; it is easy to administer and well tolerated. Identification of the molecular and genetic events involved in each step of tumor progression seems to be crucial both to understanding lung cancer and for the development of new pharmacologic compounds that target specific cellular processes affecting growth and proliferation. An innovative strategy is to combine established chemotherapy with these new compounds. Resistance to available chemotherapy drugs is the major obstacle to effective chemotherapy. Genetic abnormalities could play a role in outlining some patterns of chemoresistance. Acquired resistance to paclitaxel can be mediated by several mechanisms, including overexpression of p-glycoprotein, altered expression of beta-tubulin isotypes, intrinsic or acquired mutations in beta-tubulin, and expression of novel genes. Beta-tubulin mutations were recently identified in 33% of 49 NSCLC patients, none of whom had an objective response to paclitaxel treatment. Cisplatin resistance is associated with several molecular alterations, including overexpression of metallothionein and the mRNA level of the excision repair cross-complementing (ERCC1) gene. Early detection of circulating cancer cells in peripheral blood would enable more accurate lung cancer staging. Furthermore, sequential measurements of DNA concentration may be used to monitor the effects of therapy. Serum DNA can be used as a surrogate for detecting genetic abnormalities and as a potential guide for customizing treatment. We analyzed the presence of beta-tubulin mutations in serum DNA from NSCLC patients and from healthy individuals. Beta-tubulin mutations were detected in 42% of the 131 patients and in none of the control group. Several clinical studies are proposed to develop more customized approaches in lung cancer.
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PMID:Predicting response to paclitaxel/carboplatin-based therapy in non-small cell lung cancer. 1160 82

Paclitaxel has proven to be a useful drug for patients with advanced non-small cell lung cancer (NSCLC). Paclitaxel-based combination chemotherapy, particularly with carboplatin, has become a very popular combination in the US. This article will review the conclusions of several studies regarding paclitaxel-based chemotherapy. The data provide evidence that this therapy produces good palliation and prolongation of survival for patients with NSCLC and is superior to older cisplatin-based chemotherapy. These results in patients with advanced disease have important implications for neoadjuvant and/or adjuvant approaches in patients with lower stages of disease, and several studies are ongoing.
Lung Cancer 2001 Dec
PMID:Paclitaxel-based combination chemotherapy in advanced non-small cell lung cancer. 1174 3

Lung carcinoma is one of the most frequent causes of malignancy-related mortality in the world. Paclitaxel (PA) is an antineoplastic agent used in the treatment of non-small-cell lung cancer (NSCLC) and possesses a single-agent response rate approaching 25%. PA kills tumor cells by inducing both cellular necrosis and apoptosis. Fas and Trail receptors (DR4 and DR5) are TNF family members and act as death signal transduction proteins in the apoptosis cascade. Despite the importance of PA in lung cancer treatment, the function of Fas, DR4 and DR5 in PA-induced apoptosis, as well as the effect of their respective ligands FasL and TRAIL alone or in combination with PA, remains poorly understood. We show here that 10 microM PA induces a significant 10- to 57-fold increase in primary lung cancer cell apoptosis and is associated with 20-215% increases in caspase-3 activity in various NSCLC cell types. All the lung cancer cells express Fas, FasL, DR4 and DR5; however PA did not significantly modify their levels. We provide here the first time evidence that TRAIL is a potent inducer of apoptosis in multiple NSCLC cell lines. Noticeably, CH11, the Fas receptor cross-linking and the antagonistic anti-DR5 antibody enhance considerably the spontaneous apoptotic rate in 3 out of 5 cell types. The combination treatments, FasL+PA, TRAIL+PA or PA+anti-DR5 antibody, greatly enhance PA-apoptotic effect in most cell lines. These data suggest that the use of new combination treatment with PA and ligands targeting Fas or TRAIL receptors would be particularly efficacious.
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PMID:TRAIL, FasL and a blocking anti-DR5 antibody augment paclitaxel-induced apoptosis in human non-small-cell lung cancer. 1180 7

OBJECTIVE: To review the role of chemotherapy in advanced non-small-cell lung cancer, focusing on cisplatin-based regimens and two new drugs: paclitaxel and gemcitabine. DATA SOURCES: Medline search of the relevant English literature. STUDY SELECTION: Open and randomised comparative (phases II and III2) studies, and meta-analyses of cytotoxic drugs/regimens used to treat advanced non-small-cell lung cancer. DATA EXTRACTION: The following factors were studied and compared: symptomatic response rates; tumour response rates: median survival time and 1-year survival rates; and side effects of cisplatin-, paclitaxel-, and gemcitabine-based regimens. DATA SYNTHESIS: Using cisplatin-based chemotherapy achieves significant relief of disease-related symptoms of advanced non-small-cell lung cancer and a slight improvement in the median survival time (by approximately 1.5 months). New cytotoxic drugs that are effective and have good safety profiles include paclitaxel and gemcitabine. When used as single agents, these two drugs give response rates of approximately 25%. When used with cisplatin/carboplatin, response rates increase to 45% to 62% and 1-year survival rates increase to 40% to 60%. CONCLUSION: Paclitaxel, gemcitabine, and other drugs such as decetaxel and vinorelbine are promising new chemotherapeutic agents in the treatment of advanced non-small-cell lung cancer. These drugs can palliate disease symptoms and improve the median survival time. The optimal dose and treatment schedules, however, are yet to be defined.
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PMID:Chemotherapy for advanced non-small-cell lung cancer: role of paclitaxel and gemcitabine. 1182 89

Twenty-four patients previously treated with platinum containing regimens with stage IIIB-IV non-small-cell lung cancer (NSCLC) participated in the study. Sequential cohorts of patients were treated with 60 and 90 mg/m(2) of Paclitaxel per week. Paclitaxel was administered weekly over 1 h infusion for 6 consecutive weeks followed by 2 weeks without treatment (8-week cycle). A total of 252 treatments were administered to the 24 patients. In 29 (12%) of 252 treatments grade 2 granulocytopenia was observed while four patients (17%) developed grade 2 neuropathy. Seven patients (29%) achieved a partial response and five (21%) had stable disease. Paclitaxel 90 mg/m(2) per week as salvage treatment is well tolerated and has shown promising activity in patients with NSCLC who progress after platinum treatment.
Lung Cancer 2002 Mar
PMID:Is weekly paclitaxel superior to paclitaxel given every 3 weeks? Results of a phase II trial. 1184 7

The frequency, risk factors, pathophysiology, diagnosis, and management of lung cancer are reviewed. An estimated 157,400 Americans died of lung cancer in 2001. Lung cancer is the second most frequent cancer in both men and women. The major risk factor for lung cancer is smoking, which accounts for 75-80% of lung cancer-related deaths. Lung cancers can be broadly classified into two forms, small-cell carcinomas and non-small-cell carcinomas. Non-small-cell lung cancer is more common, accounting for up to 75% of lung cancers. Lung cancer is diagnosed by chest radiography, sputum cytology, bronchoscopy, needle biopsy, and other techniques. Surgery plays a major role in managing stage I and stage II non-small-cell lung cancer and may be used for stage III disease. Patients with stage IIIa disease may be surgical candidates, but involvement of mediastinal lymph nodes reduces the probability of survival. Adjuvant irradiation may reduce the rate of local recurrence but does not increase survival time. Adjuvant chemotherapy may confer a small survival-time advantage if the regimen includes cisplatin. Chemotherapy combined with radiation therapy may produce a survival advantage over irradiation alone. Patients with advanced non-small-cell lung cancer should receive combination chemotherapy. Several regimens have shown a survival advantage over best supportive care. Paclitaxel, docetaxel, gemcitabine, vinorelbine, irinotecan, and topotecan have activity both as single agents and in combination. Surgery has only a limited role in the management of small-cell lung cancer. Patients with limited disease should receive a platinum-based chemotherapy regimen plus radiation therapy. Combination chemotherapy should be offered to patients with extensive disease. The most active regimens contain cisplatin or carboplatin. Paclitaxel, docetaxel, gemcitabine, vinorelbine, irinotecan, and topotecan combinations have shown some promise. Lung cancer, although highly preventable, is usually diagnosed at an incurable stage. Chemotherapy is playing an increasingly important role alongside surgery and radiation therapy in the management of this disease.
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PMID:Lung cancer: a review. 1194 3

Non-small-cell lung cancer (NSCLC) has one of the highest death rates among the various forms of cancer. In attempts to improve on this unsatisfactory outcome, different radiation schedules and chemo-therapy agents have been examined in phase II or III studies. These have led to modest improvements in local control and survival, but combined therapies are associated with substantial hematologic toxicity. In this phase II study, 80 consecutive stage IIIA or IIIB NSCLC patients were treated with concomitant chemotherapy and twice-a-day irradiation in a total dose of 60 Gy in 1.5 Gy fractions. Patients scheduled for surgery received 45 Gy only. Paclitaxel (30 mg/m 2 ) on days 1-4 and cisplatin (100 mg/m 2 ) on day 5 were administered in the first and fourth weeks of treatment. Granulocyte colony stimulating factor (30 ng/m 2 ) was given on days 10-15. The local control, the 1- and 2-year survival rates and the occurrence of acute hematologic toxicity in the non-surgically treated patients were examined. Fifty-two patients were treated without and 28 with surgery. Among the non-surgically treated cases, 43 were evaluable for response and 47 for acute toxicity during a median follow-up of 22 months. The rate of local control was 65% (28/43), and the 1- and 2-year survival rates proved to be 68% and 48%, respectively, with a median survival of 28 months. Severe acute grade 3-4 toxicities included grade 4 leukopenia in 6 cases (13%), grade 3 leukopenia in 4 cases (9%), grade 3 esophagitis in 3 cases (6%) and grade 3 anemia in 3 cases (6%). Our results and the relevant data from the literature support the application of twice-a-day irradiation with concomitant chemotherapy in stage IIIA and IIIB NSCLC. Local control and survival were improved relative to once-a-day irradiation with sequential or concomitant chemotherapy.
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PMID:Concurrent paclitaxel-cisplatin and twice-a-day irradiation in stage IIIA and IIIB NSCLC shows improvement in local control and survival with acceptable hematologic toxicity. 1251 95

Anti-tubulin couplets have activity in hormone-resistant prostate cancer. This study was designed to define the dose-limiting toxicity (DLT) and recommended phase II dose (RPTD) of the unique triplet combination of paclitaxel, estramustine phosphate (EMP) and vinorelbine (Pacl-E-Vin). Patients with advanced malignancies who had failed standard therapy, ECOG performance status (PS 0-2) and adequate organ function were included. Dose of EMP was fixed at 300 mg/m2/dose p.o. t.i.d. on days 1-3 and 8-10. Vinorelbine dose was 20 mg/m2/day i.v. on days 3 and 10. Paclitaxel was dose escalated from 40 to 50 mg/m /day i.v. on days 3 and 10. Cycles were repeated every 3 weeks. Twelve adults (median age 72) were entered on this study. Primary tumors included prostate (n=7), cervix (n=2), melanoma (n=1), colon (1) and lung with synchronous prostate cancer (n=1). Nine patients had received no prior chemotherapy, one had received a prior regimen and two had received two or more prior regimens. Of four evaluable patients at dose level 1, one patient had grade 3 neutropenia leading to the day 10 dose being withheld. Of five evaluable patients at dose level 2, there was one DLT (febrile neutropenia) and two grade 3 neutropenias leading to the day 10 dose being withheld. One patient had a lower extremity deep vein thrombosis. Other side effects were mild and reversible. Nine patients were evaluable for efficacy: three with prostate cancer had a greater than 50% prostate-specific antigen (PSA) response, and a patient with synchronous prostate and lung cancer had a greater than 50% PSA response. We conclude that the DLT of Pacl-E-Vin is neutropenia. RPTD is vinorelbine 20 mg/m2, paclitaxel 40 mg/m2, both administered on days 3 and 10, and EMP 900 mg/m2/day on days 1-3 and 8-10, q3w. Dose omission at day 10 followed by 20% dose reduction of paclitaxel and vinorelbine is recommended in the event of grade 3 neutropenia. Activity in hormone-refractory prostate cancer is promising and warrants phase II evaluation.
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PMID:A phase I study of paclitaxel, estramustine phosphate and vinorelbine (Pacl-E-Vin) in advanced malignancies: triple tubulin targeting. 1254 60

The objective of the present study was to evaluate the activity and the toxicity of an original combination of paclitaxel (Taxol), ifosfamide, and carboplatin in patients with stage IIIB-IV non-small-cell lung cancer (NSCLC). Sixty-one patients with previously untreated stage IIIB-IV NSCLC were enrolled by five institutions. Paclitaxel was given at the dose of 200 mg/m iv in 3 hours, ifosfamide (with mesna) at the dose of 3 g/m and carboplatin at an area under the curve 5, on day 1, every 21 days for a total of six cycles in responding or stabilized patients. Among the 59 patients evaluable for response, 2 complete remissions and 25 partial remissions were achieved for an overall response rate of 45.7% (95% CI = 32.7-59.2). According to an intention-to-treat analysis, the response rate was 44.2%. Thirteen patients had a stable disease, whereas 19 progressed. The median time to progression was 7.7 months (range: 1-18), whereas the median overall survival was 10 months (range: 1-30+). The 1-year survival rate was 43%. Hematologic toxicity was exceptionally mild, and peripheral neurologic toxicity of grade III was experienced by only three patients. There was one toxic death. This original triplet regimen based on paclitaxel, ifosfamide, and carboplatin has proved active, safe, and easy to deliver on an outpatient basis for patients with advanced NSCLC. Randomized studies both versus carboplatin-paclitaxel and other triplets are clearly warranted.
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PMID:Phase II study of Taxol combined With ifosfamide and carboplatin in the treatment of stage IIIb-IV non-small-cell lung cancer. 1257 30


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