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 report here the preliminary results of a large phase II multicenter study done in the community setting, using paclitaxel (Taxol) (given by 1-hour infusion) plus carboplatin (Paraplatin) to treat patients with advanced non-small-cell lung cancer (NSCLC). In this study, 155 chemotherapy-naive patients with stage IIIB, stage IV, or recurrent metastatic non-small-cell lung cancer received the two drugs in 21-day cycles. Paclitaxel 225 mg/m2 was given by 1-hour intravenous infusion followed immediately by carboplatin at a targeted area under the concentration-time curve of 6.0 (calculated according to the Calvert formula). Colony-stimulating factors were not used routinely. Objective responses occurred in 53 of 155 patients (34%) (53 of 144 [36%] evaluable patients) including three complete responses and 50 partial responses. Fifty-two other patients had stable disease at initial reevaluation. The median survival among all 155 patients was 8 months; the 1-year survival rate was 42%, and the 2-year survival rate was 20%. Leukopenia and cumulative peripheral neuropathy occurred consistently but rarely were severe or affected the course of therapy. One patient died due to sepsis. Other grade 3 and grade 4 toxicities were uncommon. This paclitaxel-carboplatin combination chemotherapy appears to be a relatively convenient, safe, and active regimen in advanced non-small-cell lung cancer.
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PMID:One-hour paclitaxel plus carboplatin for advanced non-small-cell lung cancer. 951 16

Chemotherapeutic intervention in advanced and metastatic non-small-cell lung cancer (NSCLC) has changed over the past 2 decades. The improvements offered by cisplatin (Platinol)-based regimens, though significant in terms of survival and quality of life, were modest at best. Carboplatin (Paraplatin), which possesses a toxicity profile favorable to that of its parent analogue cisplatin, yielded survival rates superior to that of the cisplatin-combination chemotherapy arms in a large randomized study of patients with metastatic non-small-cell lung cancer. With the introduction of taxanes in the early 1990s, paclitaxel (Taxol) demonstrated single-agent activity of 21% to 24%, with a 40% 1-year survival rate in metastatic disease. The next generation of phase I/II studies evaluated the efficacy of paclitaxel in combination with carboplatin. Results with this regimen have shown substantial promise, and 1-year survival rates as high as 54% have been reported. Full doses of both agents have been combined without any additional toxicity, and there appears to be a dose-response effect with paclitaxel. The combination of paclitaxel and carboplatin has been incorporated as the investigational arm of all the ongoing multicenter and cooperative group studies. While the results from these randomized studies are awaited, this combination has become the most widely used regimen in community practice for patients with non-small-cell lung cancer. It is also being evaluated for treatment at earlier disease stages, in the setting of minimal tumor burden, and in combined-modality regimens.
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PMID:Paclitaxel/carboplatin in the treatment of non-small-cell lung cancer. 951 17

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

A major impediment to the successful use of Taxol in the treatment of cancer is the development of drug resistance. The major cellular target of Taxol is the microtubule that is comprised of alpha- and beta-tubulin heterodimers. Binding sites for Taxol have been delineated on the beta-tubulin subunit that has six isotypes. We have recently described increased expression of the brain-specific human class III beta-tubulin isotype, encoded by the Hbeta4 gene, in both Taxol-resistant ovarian tumours and non-small-cell lung cancer cell lines. To evaluate directly the role of the class III beta-tubulin isotype in mediating Taxol resistance, antisense phosphorothioate oligodeoxynucleotides (ODN) targeted against various regions of the Hbeta4 gene have been designed and examined for their efficacy in reducing Hbeta4 gene and protein expression. Taxol-resistant lung cancer cells, A549-T24, which are 17-fold resistant to Taxol and display a fourfold increase in Hbeta4 expression compared to the parental A549 cells, were treated with 1 microM antisense ODNs. Two ODNs, AS1 and AS3, were found to reduce mRNA expression by 40-50%, as determined by reverse transcription polymerase chain reaction. A concentration-dependent reduction in Hbeta4 mRNA expression was demonstrated with AS1 ODN. Immunofluorescence staining of cells treated with AS1 ODN revealed a decrease in class III protein expression which corresponded to a 39% increase in sensitivity to Taxol (P < 0.005). These findings support an important role for Hbeta4 (class III) beta-tubulin expression in Taxol resistance and have potential implications for the treatment of Taxol-resistant tumours.
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PMID:Antisense oligonucleotides to class III beta-tubulin sensitize drug-resistant cells to Taxol. 1036 10

We studied AG3340, a potent metalloproteinase (MMP) inhibitor with pM affinities for inhibiting gelatinases (MMP-2 and -9), MT-MMP-1 (MMP-14), and collagenase-3 (MMP-13) in many tumor models. AG3340 produced dose-dependent pharmacokinetics and was well tolerated after intraperitoneal (i.p.) and oral dosing in mice. Across human tumor models, AG3340 produced profound tumor growth delays when dosing began early or late after tumor implantation, although all established tumor types did not respond to AG3340. A dose-response relationship was explored in three models: COLO-320DM colon, MV522 lung, and MDA-MB-435 breast. Dose-dependent inhibitions of tumor growth (over 12.5-200 mg/kg given twice daily, b.i.d.) were observed in the colon and lung models; and in a third (breast), maximal inhibitions were produced by the lowest dose of AG3340 (50 mg/kg, b.i.d.) that was tested. In another model, AG3340 (100 mg/kg, once daily, i.p.) markedly inhibited U87 glioma growth and increased animal survival. AG3340 also inhibited tumor growth and increased the survival of nude mice bearing androgen-independent PC-3 prostatic tumors. In a sixth model, KKLS gastric, AG3340 did not inhibit tumor growth but potentiated the efficacy of Taxol. Importantly, AG3340 markedly decreased tumor angiogenesis (as assessed by CD-31 staining) and cell proliferation (as assessed by bromodeoxyuridine incorporation), and increased tumor necrosis and apoptosis (as assessed by hematoxylin and eosin and TUNEL staining). These effects were model dependent, but angiogenesis was commonly inhibited. AG3340 had a superior therapeutic index to the cytotoxic agents, carboplatin and Taxol, in the MV522 lung cancer model. In combination, AG3340 enhanced the efficacy of these cytotoxic agents without altering drug tolerance. Additionally, AG3340 decreased the number of murine melanoma (B16-F10) lesions arising in the lung in an intravenous metastasis model when given in combination with carboplatin or Taxol. These studies directly support the use of AG3340 in front-line combination chemotherapy in ongoing clinical trials in patients with advanced malignancies of the lung and prostate.
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PMID:Broad antitumor and antiangiogenic activities of AG3340, a potent and selective MMP inhibitor undergoing advanced oncology clinical trials. 1041 35

Esophagitis is a major toxicity of radiation therapy for nonsmall-cell lung cancer. Intraesophageal injection of manganese superoxide dismutase (MnSOD) plasmid/liposome complexes (1 mg of the pRK5-MnSOD plasmid containing the human MnSOD transgene in a 0.15 ml volume of lipofectin) before irradiation was carried out to attempt to prevent irradiation esophagitis. In control noninjected male C3H/HeNsd mice, esophagitis was induced by single fraction 3,500 cGy irradiation. Histopathology at 4 days revealed vacuole formation in squamous lining cells, separation of the squamous layer from the underlying muscle layer, ulceration at 7 days, and dehydration and death by 30 days. MnSOD plasmid/liposome complex-injected mice showed transcription of the human MnSOD transgene message in esophageal squamous lining cells by nested reverse transcriptase-polymerase chain reaction (RT-PCR) increased MnSOD biochemical activity 24 h after injection, decreased vacuole formation at day 4 (P < 0.001) after 3,500 cGy thoracic irradiation, and improved survival (P = 0.0009). In contrast, groups of mice receiving LacZ (bacterial beta-galactosidase gene) plasmid/liposome complexes or liposomes containing no DNA before 3,500 cGy irradiation showed an unaltered irradiation histopathology and decreased survival. Mice receiving intraesophageal MnSOD plasmid/liposomes followed 8 h later by human equivalent doses of Taxol (1.4 mg/kg) and carboplatin (2.5 mg/kg), then 15 h later 3,300 cGy irradiation, showed increased survival, compared with irradiated control or LacZ plasmid/liposome groups. Thus, overexpression of the human MnSOD transgene in the esophagus can prevent irradiation-induced esophagitis in the mouse model.
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PMID:Prevention of irradiation-induced esophagitis by plasmid/liposome delivery of the human manganese superoxide dismutase transgene. 1049 61

The optimal therapy for locally advanced, unresectable, stage III non-small-cell lung cancer (NSCLC) continues to evolve. The critical determinants of overall survival include local tumor control and the eradication of subclinical micrometastatic disease. Historically, standard radiation therapy resulted in a median survival of 7 to 10 months. In a randomized trial, the Cancer and Leukemia Group B (CALGB) established the superiority of induction cisplatin (Platinol) and vinblastine chemotherapy followed by radiation therapy. Additional studies revealed that induction chemotherapy improved survival rates by decreasing metastatic disease progression. Three independent meta-analyses confirmed the survival benefit afforded by cisplatin-based induction chemotherapy followed by radiotherapy, and helped to establish this as the new standard of care. Other investigators have demonstrated improvements in local tumor control and survival with either concurrent chemoradiotherapy or hyperfractionated radiotherapy. Most recently, attention has focused on radiation dose intensity and the utilization of newer, highly active chemotherapeutic agents with concurrent or sequential radiation therapy. These newer drugs, including paclitaxel (Taxol), docetaxel (Taxotere), gemcitabine (Gemzar), vinorelbine (Navelbine), and irinotecan (Camptosar), enhance radiation cytotoxicity and, when administered in systemically active dosages, may also control micrometastatic disease. Phase I and II studies of novel chemoradiation regimens continue to demonstrate encouraging results, and several large randomized clinical trials are currently enrolling patients.
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PMID:Chemoradiation for locally advanced, unresectable NSCLC. New standard of care, emerging strategies. 1049 43

Paclitaxel (Taxol; Bristol-Myers Squibb) is one of the most active single agents for non-small cell lung cancer (NSCLC), and ideal in combination with radiation therapy. We designed a phase II study to determine the efficacy and toxicity of continuous hyperfractionated accelerated radiotherapy (CHART) and concurrent weekly Paclitaxel (T) in good performance status patients with unresectable stage III A and B NSCLC. T (60 mg/m2) was given as a 3-h infusion on days 1, 8, 15, 22, 29 and 36; CHART was started on day 15 with 150 cGy/fraction given three times a day for a total dose of 54 Gy in 12 days with no weekend break. Twenty patients were evaluable for acute toxicity. The major acute toxicities were esophagitis and pulmonary toxicity; 70% of the patients experienced grade 2-3 esophagitis and 50% experienced grade > or = 3 pulmonary toxicity. Grade 3 anemia developed in only one patient. Of the 17 patients evaluable for late toxicity, 12% of the patients had grade 3 pulmonary toxicity, one patient developed grade 4 esophagitis. Nineteen patients were evaluable response. The overall response rate was 84% (95% confidence interval, 60-97). CHART with concurrent weekly T seems to be an effective regimen, but tolerability needs to be documented with a larger number of patients and longer follow-up.
Lung Cancer 1999 Sep
PMID:Preliminary analysis of a phase II study of Paclitaxel and CHART in locally advanced non-small cell lung cancer. 1051 30

Lung cancer is the leading cause of cancer death in the United States. Surgery is the treatment of choice for early stage patients. Despite radical surgery, patients with early stage lung cancer remain at risk for recurrence. The role of adjuvant therapy remains to be clearly defined. Locally advanced non-small-cell lung cancer is too extensive for surgical resection, yet does not show evidence of metastatic disease. Historically, these patients were treated with radiation alone. More recent studies have provided the rationale for combining radiation with chemotherapy for patients with good performance status who have locally advanced disease. For patients with marginally resectable tumors, treatment is often given preoperatively (neoadjuvant) as a means of shrinking the tumor to make it resectable. In patients with clearly unresectable disease, radiation with chemotherapy has been established as better than either modality alone. Palliative radiation alone can be used for patients who cannot tolerate this aggressive approach. The optimal sequencing, as well as the best chemotherapeutic agent to use, remains under investigation. Some of the newer agents showing promise in the treatment of non-small-cell lung cancer include paclitaxel (Taxol) and carboplatin (Paraplatin). Other agents that are currently under investigation include topotecan, gemcitabine, and vinorelbine (Navelbine).
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PMID:The role of radiation, with or without chemotherapy, in the management of NSCLC. 1055 Aug 32


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