| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Guest Access | Sign In via User Name/Password
|
|
|
|||||||
Guest Access | Sign In via User Name/Password |
|||||||||
* From the Divisions of Medical Oncology (Drs. Molina and Adjei) and Pulmonary Medicine (Dr. Jett), Mayo Clinic College of Medicine, Rochester, MN.
Correspondence to: Julian R. Molina, MD, PhD, Mayo Clinic and Foundation, Rochester, MN 55905; e-mail: molina.julian{at}mayo.edu
Abstract
In the United States, lung cancer kills more men and woman than the next three most common cancers combined. Unfortunately, the long-term outcome of lung cancer is still dismal with a 5-year survival rate of 15%. However, significant improvements in median survival times and 1-year and 2-year survival rates have been achieved in the last decade. This progress has been accomplished not only because of better surgical techniques but also because of the use of platinum-based regimens with newer chemotherapy agents and, more recently, targeted therapy. The role of chemotherapy as an integral part of the treatment of lung cancer has expanded significantly, particularly in the last few years with the proven benefit of adjuvant chemotherapy. For advanced stage non-small cell lung cancer (NSCLC), chemotherapy prolongs survival and improves quality of life in patients with good performance status, and appears to provide symptomatic improvement in patients with decreased performance status. Platinum-based doublet chemotherapy regimens are now the standard of care in patients with advanced stage NSCLC, and non-platinum-based combination therapies are reasonable alternatives in certain populations. The combination of the vascular endothelial growth factor inhibitor bevacizumab and chemotherapy has proven to prolong survival. As agents such as monoclonal antibodies, small molecules inhibitors of tyrosine kinase, and direct inhibitors of proteins involved in lung cancer proliferation are being developed and tested, we are optimistic that these agents will result in improvement in the survival and quality of life of lung cancer patients.
Key Words: chemotherapy • lung cancer • targeted therapy
Lung cancer continues to be the leading cause of cancer-related mortality for both men and women in the United States. In 2005, 172,570 new cases of lung cancer were diagnosed and 163,510 resulted in death.1 Lung cancer surpassed breast cancer as the leading cause of cancer death in women in 1987, and currently kills more women than breast and colorectal cancer combined. Although lung cancer-related mortality in men has declined in the last 10 years, lung cancer still results in the death of more men than prostate, pancreatic, and colorectal cancers combined.1 Close to 70% of patients with lung cancer present with locally advanced or metastatic disease at the time of diagnosis.
Chemotherapy is beneficial for patients with locally advanced and metastatic disease.2 Adjuvant chemotherapy is generally indicated for patients with resected stages IB through IIIA non-small cell lung cancer (NSCLC). In the past decade, newer agents such as gemcitabine (GEM), vinorelbine (VNR), paclitaxel (PTX), and docetaxel (DTX) have all demonstrated activity against NSCLC as single agents; consequently, these agents have been combined with cisplatin (CDDP) or carboplatin (CBDCA). Randomized phase III trials comparing these "newer" platinum-based doublets have shown that platinum-based doublets are equally effective.
Though it is clear that chemotherapy is an appropriate treatment for many patients with lung cancer, there is a sense that the use of traditional chemotherapeutic agents has reached a therapeutic plateau. Increased understanding of cancer biology has revealed numerous potential therapeutic strategies, including targeting the epidermal growth factor receptor (EGFR) protein kinase C, rexinoid receptors, and the angiogenesis pathways. The use of the targeted agent bevacizumab in combination with other chemotherapy agents resulted in significantly longer survival times for patients with advanced NSCLC.3
Adjuvant Chemotherapy for Resected Early-Stage NSCLC
Patients with resected lung cancer carry a high risk of relapse. A metaanalysis4 conducted in 1995 using updated data on individual patients from 52 randomized clinical trials compared outcomes of patients after surgery alone vs surgery followed by chemotherapy. This metaanalysis4 showed a 5-year survival benefit of borderline significance for patients receiving platinum-based chemotherapy and prompted the initiation of several lung cancer adjuvant trials (Table 1 ). Initial trials such as the Adjuvant Lung Project Italy5 and the Big Lung Cancer Trial6 failed to prove a survival advantage for patients receiving adjuvant chemotherapy. However, at least four subsequent trials78910 yielded a survival advantage with adjuvant chemotherapy. The International Adjuvant Lung Cancer Trial (IALT)7 is the largest of these adjuvant trials. A total of 1,867 patients with resected stage IA-IIIA cancer were randomized to receive platinum-based chemotherapy or observation. The selection of the second agent (eg, etoposide, VNR, vinblastine, or vindesine) and the use of radiotherapy after chemotherapy were allowed, and varied by center. After a median follow-up period of 56 months, there was a 4.1% absolute survival benefit at 5 years and a 14% relative reduction in risk of death (hazard ratio, 0.86; 95% confidence interval, 0.76 to 0.98; p < 0.03). The survival advantage observed with chemotherapy was not associated with the use of radiation, the choice of a second drug (50% of patients received etoposide), dose of CDDP, or covariates such as disease stage.7 The National Cancer Institute of Canada intergroup study JBR.108 included 482 patients with completely resected stage IB and II (excluding T3N0) cancers. Patients in this trial were randomized to receive four cycles of adjuvant VNR and CDDP or observation alone. Adjuvant radiation therapy was not allowed. Overall survival strongly favored patients in the adjuvant chemotherapy arm with an absolute survival benefit of 15% at 5 years and a 30% relative reduction in the risk of death (p = 0.012).8 The Cancer and Leukemia Group B (CALGB) trial 96339 enrolled 344 patients with resected stage IB NSCLC. Patients were randomized to receive four cycles of adjuvant PTX and CBDCA or observation alone. At a median follow-up time of 34 months, a statistically significant survival advantage was detected for the chemotherapy arm with an absolute benefit of 12% at 4 years.9 However, a 5-year updated report on this trial9 no longer shows a significant overall survival advantage for patients with stage IB NSCLC receiving adjuvant chemotherapy. The most recently reported adjuvant trial is the Adjuvant Navelbine International Trialist Association trial.10 This study was performed in Europe and randomized 840 patients with completely resected stage IB, II, or IIIA NSCLC to receive adjuvant therapy with VNR and CDDP or observation alone. The Adjuvant Navelbine International Trialist Association trial10 allowed participating institutions to deliver radiotherapy if this was part of their postoperative protocol. After a median follow-up time of > 70 months, a statistically significant survival advantage was detected for patients with adjuvant chemotherapy with an absolute overall survival benefit of 8.6% at 5 years. Survival by treatment stage was given; however, no statistical analysis was reported (5-year survival rate for chemotherapy group: stage IB, 62%; stage II, 52%; stage IIIA, 42%; 5-year survival rate for control group: stage IB, 63%; stage II, 39%; stage IIIA, 26%).10 The results of these four randomized trials clearly support the use of chemotherapy after complete resection of stages IIA to IIIA lung cancer. Whether these recommendations can be applied to a patient with resected stage IA and IB lung cancer is still unclear, as patients with stage IA lung cancer were only included in the IALT trial and the results of the update of CALGB trial 96339 were negative. The IALT7 demonstrated a tendency in favor of survival for patients with stage IA lung cancer receiving a platinum-based regimen. Several trials performed in Japan have addressed the issue of adjuvant chemotherapy for early-stage lung cancer. These studies have utilized an oral agent that combines tegafur (a 5-fluorouracil prodrug) and uracil in a 1:4 mol/L ratio (uracil/tegafur [UFT], which is given as single agent or in combination with other chemotherapy agents.1112131415161718 UFT is not available in the United States. In one of these studies,17 UFT was given to 979 patients with resected stage I lung cancer. This study showed a survival benefit in favor of the UFT arm (Table 1). However, a subset analysis18 demonstrated that the benefit was limited to patients with stage IB lung cancer. Thus, future studies are needed to better determine the role, if any, of adjuvant chemotherapy in patients with stage IA resected lung cancer.
|
For patients with clinical stage IIIB unresectable NSCLC, combined-modality treatment has become the standard of therapy in the past few years. Two treatment strategies, induction chemotherapy and concurrent chemoradiotherapy, have demonstrated favorable effects on survival and are superior to radiotherapy alone. Several groups of investigators have directly compared the two treatment strategies in phase III clinical trials. The first published data came from Japanese investigators19 who compared the use of sequential chemoradiotherapy with that of concurrent chemoradiotherapy. The median survival time was 16 months vs 13 months for the concurrent administration. Similar results were observed in the Radiation Therapy Oncology Group study 9410,20 which showed superior 5-year survival rates with concurrent therapy compared to sequential therapy with CDDP and vinblastine. Based on these results, concurrent chemoradiotherapy is considered by many to be the preferred strategy for the treatment of stage III NSCLC. In the Southwest Oncology Group (SWOG) phase II study 9504,21 concomitant chemoradiotherapy with CDDP and etoposide was followed by three cycles of DTX as consolidation chemotherapy in 83 patients with stage IIIB disease. This regimen was associated with a median survival time of approximately 2 years and a favorable 5-year survival rate of 29%. The role of induction chemotherapy in the context of concurrent chemoradiotherapy was examined in CALGB study 39801.22 The addition of induction chemotherapy to concomitant chemoradiotherapy of PTX and CBDCA did not significantly impact survival outcomes.22 These observations suggest that concurrent chemoradiation should be the standard of care. The benefit gained by adding consolidation chemotherapy, as suggested by SWOG 9504,21 remains to be confirmed in phase III trials.
Treatment of Metastatic Lung Cancer
A myriad of phase III studies have determined the superiority of systemic chemotherapy over best supportive care in patients with locally advanced and metastatic lung cancer. Platinum-based chemotherapy has been widely accepted as the standard of care. Several randomized clinical trials as well as metaanalyses have suggested the superiority over non-platinum-based therapy.2324 A landmark metaanalysis23 included 778 patients from eight clinical trials who were treated either with CDDP-based chemotherapy or best supportive care. CDDP-based chemotherapy resulted in increased median survival time (1.5 months) and a hazard ratio for death of 0.73 in favor of CDDP (p < 0.0001).23 Agents such as PTX, DTX, GEM, and VNR have been incorporated into platinum-based therapy doublets and been proven to be equally effective. For example, Eastern Cooperative Oncology Group trial 1594 (E1594)25 was a trial designed to compare four platinum-based regimens in > 1,000 patients with stage IIIB and IV NSCLC (Table 2 ). In this trial,25 a standard regimen of PTX plus CDDP was compared with CDDP plus GEM, CDDP plus DTX, and CBDCA plus PTX. Results from this trial25 showed no significant differences among the regimens with respect to overall survival time. Response rates ranged from 17% with CDDP + DTX and CBDCA + PTX therapy, to 21 to 22% with CDDP + PTX and CDDP + GEM therapy. The overall response rate did not differ among groups. Ultimately, the trial25 demonstrated no significant advantage of one regimen over the others. The SWOG trial 9509 (SWOG 9509)26 compared therapy with CBDCA + PTX) with therapy with CDDP + VNR in 408 eligible patients with advanced NSCLC. The median survival times as well as the 1-year or 2-year survival rates were similar but had more toxicity in the CDDP + VNR arm.26 The Italian Lung Cancer Project27 was a randomized trial of 612 patients that compared therapy with CDDP + VNR with therapy with CDDP + GEM and CBDCA + PTX. Response and survival rates were similar among the three groups (Table 1).27
|
Due to the toxicities associated with platinum-based chemotherapy, non-platinum-based regimens, in particular taxane-based regimens, have been the focus of intense research. A recent randomized study28 of 413 patients compared a platinum-based regimen, CDDP + VNR, with a non-platinum-based regimen, DTX + GEM. The median survival time was similar between the two studies (CDDP + VNR, 9.7 months; DTX + GEM, 9.0 months), but toxicity was higher in the CDDP + VNR arm. The results of this study were later confirmed by a French trial29 of 311 patients randomized to receive CDDP + VNR or DTX + GEM chemotherapy regimens. Taxane-based chemotherapy in combination with GEM (ie, PTX + GEM therapy) has also proven to be equally effective when compared to CBDCA + GEM or PTX + CBDCA therapy.3031
A comparison of a GEM-based regimen (GEM + VNR) to a platinum-based therapy (VNR + CDDP and GEM + CDDP) performed by National Cancer Institute of Canada and the Italian Gemcitabine Vinorelbine group32 resulted in similar response rates and quality-of-life scores in the three arms. More hematologic toxicity, renal toxicity, and ototoxicity was seen in the platinum arm, but more hepatic toxicity was seen in the GEM + VNR arm. The study concluded that the GEM + VNR regimen is an alternative to platinum-based therapy.32
A metaanalysis33 comparing platinum-based to non-platinum-based chemotherapy in patients with advanced NSCLC was recently published. This study analyzed 37 randomized phase II and III clinical trials comparing first-line palliative platinum-based chemotherapy in 7,633 patients. A 62% increase in the odds ratio for response was attributable to platinum-based therapy (odds ratio, 1.62; 95% confidence interval, 1.46 to 1.8; p < 0.0001). The 1-year survival rate was increased by 5% with platinum-based regimens (34% vs 29%, respectively). No statistically significant increase in the 1-year survival rate was found when platinum-based therapies were compared to third-generation-based combination regimens.33 The toxicity of platinum-based regimens was significantly higher for hematologic toxicity, nephrotoxicity, and nausea and vomiting, but not for neurotoxicity, febrile neutropenia rate, or toxic death rate. The study concluded that when compared with third-generation-based combination regimens, platinum-based regimens do not result in a 1-year survival rate advantage but are associated with higher toxicity.33
The most recent treatment guidelines from the American Society of Clinical Oncology34 reflect the growing acceptance by the oncology community that nonplatinum doublets may provide advantages for certain patients. The American Society of Clinical Oncology currently allows the primary oncologist to decide between a platinum-based and a non-platinum-based chemotherapy regimen for the initial treatment of patients with stage IV disease and good performance status.34 There is currently no role for three-drug cytotoxic combination regimens in the management of advanced NSCLC; clinical trials have demonstrated that combination regimens consisting of three cytotoxic drugs produce greater toxicity without improving outcomes in this setting.
Targeted Therapy
Alteration of the major cell-signaling and regulatory pathways either by overexpression or gene mutation is a frequent event in lung cancer. These include alterations in receptor tyrosine kinases (RTKs) such as the EGFR, alterations in angiogenesis pathways, apoptosis, proteosome regulation, and cell cycle control, among others.
EGFR Inhibitors
The EGFR is overexpressed in 40 to 80% of patients with NSCLC, and its overexpression is associated with a poor prognosis.35 Several EGFR inhibitors have been developed over the last few years. These inhibitors are in either the RTK domain or are monoclonal antibodies.
RTK inhibitors are oral agents that compete with the adenosine triphosphate catalytic site and block downstream signals. Gefitinib (Iressa, ZD1839; AstraZeneca; Wilmington, DE) is the first targeted therapy to be registered and later approved by the US Food and Drug Administration (FDA) for use in lung cancer.36 Two phase II trials, Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL) trial 1 and IDEAL-2, evaluated the effects of therapy with single-agent gefitinib, 250 or 500 mg orally per day, in pretreated patients with NSCLC and found that about 20% of patients in the IDEAL-137 trial and 1% and 10% of patients in the IDEAL-2 trial38 had major objective responses and improvement of symptoms. The data from the IDEAL trials3738 and the extensive experience from the 21,000 patients treated in the expanded access program suggested that the patients who had a major objective response probably had a significant survival benefit in addition to a palliative benefit.36 Based on these results, gefitinib was granted US FDA approval for use as a third-line agent in the treatment of NSCLC. Unfortunately, the results from two phase III randomized trials of gefitinib failed to provide a survival benefit for Gefitinib when compared to placebo. The Iressa Survival Evaluation in Lung Cancer study39 was a randomized phase III study comparing daily therapy with 250 mg of gefitinib vs placebo. This study of 1,692 patients who were refractory to chemotherapy failed to demonstrate an improvement of survival time with gefitinib therapy in the overall population (median improvement, 5.6 vs 5.1 months, respectively; p = 0.11) or in patients with adenocarcinoma (median improvement, 6.3 vs 5.4 months; p = 0.07). There was, however, a benefit shown in Asians and never-smokers. The second study was SWOG 0023,40 which was a phase III randomized study in patients with stage IIIB NSCLC that was intended to demonstrate the potential benefit of maintenance gefitinib therapy over placebo after chemoradiation and consolidation chemotherapy. This study was closed after an unplanned interim analysis demonstrated no survival benefit and a potential detrimental effect for gefitinib therapy at a daily dose of 250 mg.
Erlotinib (OSI 774, Tarceva; OSI Pharmaceuticals; Melville, NY) is another EFGR tyrosine kinase (TK) inhibitor with a slightly different pharmacologic profile. Erlotinib was recently approved by the US FDA for second-line or third-line treatment of NSCLC. In a phase II trial41 of 57 patients with refractory NSCLC, erlotinib was administered as monotherapy with an objective response rate of 12.3% and a median survival time of 8.4 months. The response rate did not correlate with prior exposure to chemotherapy, but a survival advantage was observed for patients with skin toxicity. These results were later confirmed by BR21,42 which was a phase III study that randomized 731 patients who had not responded to first-line or second-line chemotherapy with erlotinib or to placebo. The overall response rate to erlotinib compared with placebo was statistically significant at 8.9%, and produced a median survival time of 6.7 months compared with 4.7 months in the placebo group (p = 0.001).42 Based on these results, the US FDA approved the use of erlotinib for patients with locally advanced or metastatic NSCLC who had not responded to one previous round of therapy. It is important to note that although erlotinib has shown a single-agent survival advantage over placebo, two randomized phase III trials (Tarceva Lung Cancer Investigation trial43 and Tarceva Responses in Conjunction with Taxol and Carboplatin trial44) that were designed to evaluate the benefit of erlotinib in combination with chemotherapy (CDDP + GEM or CBDCA + PTX) as first-line therapy for advanced NSCLC yielded negative results. There is currently no role for combining an EGFR-TK inhibitor with chemotherapy as the initial therapy for NSCLC.
EGFR Gene Mutations and Response to EGFR-TK Inhibitors
The observation that certain subgroups of patients, mainly female patients, never-smokers, patients with adenocarcinoma histology, and patients of Asian origin have a higher response rate and clinical benefit with gefitinib and erlotinib therapy prompted research to elucidate the molecular mechanism responsible for this increased response. Three different research groups have presented studies showing a positive relationship between the presence of activating mutations in the EGFR TK domain and a clinical response to gefitinib.454647 The most common mutations were in-frame deletions that resulted in the insertion of a serine residue in three mutations (del E746-A750, delL747-T751insS, and delL747-P753insS) on exon 19. Other mutations consisted of an amino acid substitution within exon 21 (leucine to arginine [L858R] and leucine to glutamine [L861Q]). EGFR mutations (L858R and delL747-P753insS) had increased TK activity compared with wild-type receptors and were more sensitive to inhibition by gefitinib. These data suggested that adenocarcinomas from never-smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity. Sordella et al48 demonstrated that EGFR mutations such as L858R and delL747-P753insS selectively activate antiapoptotic pathways by way of the increased phosphorylation of EGFR downstream effectors, Akt and STAT, but do not affect the extracellular signaling pathways of EFGR. They postulated that the effectiveness of gefitinib in lung cancers harboring mutant EGFRs may reflect both its inhibition of critical antiapoptotic pathways, on which these cells have become strictly dependent, as well as altered biochemical properties of the mutant receptors.48
Vascular Endothelial Growth Factor Inhibitors
Vascular endothelial growth factor (VEGF) binds to the VEGF receptors (VEGFRs) VEGFR-1 (Flt-1) and VEGFR-2 (kinase insert domain-containing receptor) on vascular endothelial cells. It should be noted that the activation of VEGFR-2 alone is necessary and sufficient to affect the VEGF-induced processes of mitogenesis, angiogenesis, and vascular permeability. VEGFRs are transmembrane receptors that possess intrinsic RTK activity within the cytoplasmic domain of the receptor. Ligand binding results in VEGFR dimerization, which in turn triggers kinase activation and the autophosphorylation of specific intracellular VEGFR tyrosine residues. Autophosphorylation at these tyrosine residues further increases the catalytic activity of the TK and provides potential docking sites for cytoplasmic signal transduction molecules. These protein interactions are essential for mediating the intracellular signaling that is required to induce cellular responses to VEGF.
VEGF Inhibitors Plus Chemotherapy
Prior attempts to successfully combine chemotherapy and targeted therapy in lung cancer were unsuccessful. In fact, there have been several negative studies of comparisons of standard chemotherapy doublet and targeted therapy that have included agents such as EGFR inhibitors, antisense molecules, immune modulators, and others to first-line regimens. Eastern Cooperative Oncology Group trial E45993 was the first to show a survival advantage with the addition of a targeted agent to standard chemotherapy in lung cancer. Trial E4599 combined the monoclonal antibody bevacizumab (Avastin; Genentech; South San Francisco, CA), which targets VEGF, with chemotherapy (CBDCA + PTX) and demonstrated significantly longer survival times for patients with advanced nonsquamous NSCLC. This trial compared therapy with CBDCA + PTX, which is the most common chemotherapy regimen prescribed in North America for lung cancer, with therapy with CBDCA, PTX, plus bevacizumab in 855 patients with advanced or recurrent NSCLC. Patients with squamous cell histology, hemoptysis at baseline, and brain metastases, or those receiving anticoagulation therapy were excluded from the trial because these characteristics were associated with a higher risk for bleeding in the phase II trial.49 Both response and survival parameters were significantly better with the addition of bevacizumab to chemotherapy. There was a slightly but significantly higher rate of serious bleeds in the chemotherapy-plus-bevacizumab arm of the study. A hemorrhage of grade 3 or greater occurred in 4.5% of patients in the chemotherapy-plus-bevacizumab arm but in only 0.7% in the chemotherapy-only arm (p < 0.001). Deaths attributed to treatment occurred in 2 of 427 patients in the chemotherapy only arm (GI bleed and neutropenic fever) and 8 of 420 patients in the chemotherapy-plus-bevacizumab arm (hemoptysis, 5 patients; GI bleed, 2 patients; neutropenic fever, 1 patient). Hypertension was more common in the bevacizumab treatment arm (6% vs 0.7%, respectively; p < 0.001). Hypertension is likely to be a class effect of the antiangiogenesis agents. Grade 4 neutropenia and thrombocytopenia were also significantly greater with the addition of bevacizumab, occurring in 24% and 1.4%, respectively, of patients in this arm, compared with 16.4% and 0%, respectively, of patients in the chemotherapy-only arm. Based on these results, US FDA approval is likely to be granted for use in the treatment of lung cancer in combination with chemotherapy.
Summary
Chemotherapy is the treatment of choice for most patients with metastatic NSCLC. Doublet chemotherapy regimens have been evaluated in phase III clinical trials and have generally been found to have equal efficacy. Encouraging data have been reported with nonplatinum doublet regimens in this setting as well, mostly with taxane-GEM doublets. The addition of the anti-VEGF monoclonal antibody bevacizumab to chemotherapy represents the first time that a targeted therapy has improved patient survival when added to chemotherapy for the treatment of advanced NSCLC. Several new agents such as sorafenib, PTK-787, AZD2171, and numerous other signal transduction inhibitors are currently in development, and likely will result in additional survival benefit for patients with NSCLC.
Footnotes
Abbreviations: CALGB = Cancer and Leukemia Group B; CBDCA = carboplatin; CDDP = cisplatin; DTX = docetaxel; EGFR = epidermal growth factor receptor; FDA = Food and Drug Administration; GEM = gemcitabine; IALT = International Adjuvant Lung Cancer Trial; IDEAL = Iressa Dose Evaluation in Advanced Lung Cancer; NSCLC = non-small cell lung cancer; PTX = paclitaxel; RTK = receptor tyrosine kinase; SWOG = Southwest Oncology Group; TK = tyrosine kinase; UFT = uracil/tegafur; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor; VNR = vinorelbine
Learning Objectives: Significant improvements in median survival and 1 and 2-year survival rates in patients with lung cancer are due in part to the use of platinum-based regimens with newer chemotherapy agents and targeted therapy, including the vascular endothelial growth factor (VEGF) inhibitor bevacizumab. New agents such as monoclonal antibodies, small molecule inhibitors of tyrosine kinase, and direct inhibitors of proteins involved in lung cancer proliferation are being developed and may improve outcomes in patients with lung cancer.
The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Received for publication March 28, 2006. Accepted for publication May 12, 2006.
References
This article has been cited by other articles:
|
|
 |
|
  M. S. Lee, L. Johansen, Y. Zhang, A. Wilson, M. Keegan, W. Avery, P. Elliott, A. A. Borisy, and C. T. Keith The Novel Combination of Chlorpromazine and Pentamidine Exerts Synergistic Antiproliferative Effects through Dual Mitotic Action Cancer Res., December 1, 2007; 67(23): 11359 - 11367. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
