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PubMed2006

Optimizing therapy in previously treated non-small cell lung cancer.

The past decade has seen the identification of several novel cytotoxic agents. More recently, targeted therapies with single-agent activity or that enhance the efficacy of chemotherapy in advanced non-small cell lung cancer have been identified. These agents have been, or are undergoing, active testing alone and in combination in both loco-regional and advanced disease as initial therapy and after failure of cytotoxic therapy. The cytotoxic agents docetaxel, pemetrexed, and topotecan, as well as the epidermal growth factor receptor tyrosine kinase inhibitors erlotinib and gefitinib, have been evaluated in phase III trials in previously treated populations. This review summarizes the results of these phase III studies with a particular focus on predictors of favorable outcome, attempts to provide a rational approach to therapeutic selection in this patient population, and discusses ongoing pivotal trials and future strategies in this field.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Second-line treatment options in advanced non-small cell lung cancer: current status.

Despite the emergence of several antineoplastic drugs with activity in advanced non-small cell lung cancer (NSCLC), real progress with first-line therapy has been limited in the last decade. It has proven difficult to demonstrate important differences between third generation two-drug combinations. In contrast, progress with second-line therapy has been significant, especially in the past few years, with pemetrexed showing equivalent activity to docetaxel but with substantially less toxicity. At the same time, much work has been undertaken investigating the efficacy of the small-molecule epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib in the second-line and subsequent-line settings. Erlotinib has been shown to significantly improve survival versus placebo following failure on one or two prior regimens, especially in select or targeted patient populations. Finding the optimal place and patients for these agents in NSCLC treatment will be one of the more fascinating challenges of the next few years.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

The role of gemcitabine in the treatment of malignant mesothelioma.

Gemcitabine is broadly active in a variety of solid tumors, including malignant mesothelioma. In vitro, gemcitabine demonstrates activity against mesothelioma cell lines. The role of single-agent gemcitabine in patients with mesothelioma is unclear, since three phase II trials treated a total of 60 patients and achieved response rates of 0%, 7%, and 31%. The combination of gemcitabine and cisplatin is synergistic against mesothelioma cell lines in vitro. Gemcitabine in combination with cisplatin or carboplatin shows definite activity in phase II trials. The trial by Byrne and colleagues that demonstrated a response rate of 48% established the combination of gemcitabine plus cisplatin as a standard therapy for this disease in the United States. Subsequent multicenter trials have achieved lower response rates of 26% and 16% for this combination. Gemcitabine plus carboplatin also has activity. Future roles for gemcitabine in malignant mesothelioma patients include incorporating a gemcitabine/platinum regimen for neoadjuvant or adjuvant therapy, combining it with other cytotoxic chemotherapy agents such as pemetrexed or vinorelbine, or adding novel cytostatic agents such as the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, to the gemcitabine and platinating agent combination.

Antimetabolites, Antineoplastic↗
PubMed2002

Future directions in the treatment of pancreatic cancer.

Fewer than 20% of patients with pancreatic cancer present with disease macroscopically confined to the pancreas, and approximately 40% already have locally advanced disease. Based on data from the Gastrointestinal Tumor Study Group, adjuvant therapy with radiation and 5-fluorouracil has become standard practice in the United States; however, in other countries, adjuvant treatment has not been as widely accepted. Other issues include the potential of neoadjuvant therapy and optimal systemic management. The issue of second-line therapy has also been raised in the treatment of pancreatic carcinoma, after the establishment of gemcitabine as a first-line standard treatment approach, in which it achieves a significant clinical benefit response. Other combination partners with gemcitabine under investigation include the antimetabolite 5-fluorouracil, the topoisomerase-I inhibitor irinotecan, the taxane docetaxel, the platinum oxaliplatin, the multitargeted antifolate pemetrexed, the farnesyl transferase inhibitor R-115777, the anti-HER2/neu antibody trastuzumab, and the epidermal growth factor inhibitor cetuximab. Combined-modality approaches with gemcitabine and radiation are also under active investigation.

Antimetabolites, Antineoplastic↗
PubMed2006

In vitro studies on gemcitabine combinations with other antiblastics.

The use of gemcitabine in combination with chemotherapeutic agents, including cisplatin, pemetrexed and taxanes, is characterized by the enhancement of their anticancer activity. The analysis of the underlying pharmacodynamics has revealed that modulation of nucleotide pools, drug metabolism, and cellular DNA repair capability are the most common factors to explain the additive to synergistic interaction between gemcitabine and anticancer agents in several human cancers in vitro and in vivo.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

New agents for treatment of advanced transitional cell carcinoma.

The prognosis for any patient with progressive or recurrent invasive transitional cell carcinoma remains poor. In this context, the focus of clinical research in these invasive cancers concentrates on identifying systemic treatment options and new agents in order to improve survival of patients. Cisplatin-based chemotherapy is standard treatment of patients with metastatic urothelial cancer; however, despite regimens as the cisplatin-gemcitabine combination, the overall response rates vary between 40% and 65%, with complete response in 15%-25% with survivals up to 16 months. This survival is frequently achieved with severe and life-threatening side effects. None the less, almost all responding patients relapse within the first year; therefore, the need for development of new and tolerable agents is urgent. This review highlights some new active chemotherapeutic as new platinum compounds (oxaliplatin, lobaplatin), gallium nitrate, ifosfamide, the antifolates piritrexim and pemetrexed (Alimta, LY231514), vinflunine and molecular targeting agents such as farnesyltransferase inhibitors (lonafarnib, R115777, SCH66336), ribozyme (RPI.4610), histone deacetylase inhibitor (CI-994) and monoclonal antibodies (epidermal growth factor receptor, Her 2/neu).

Antibodies, Monoclonal↗
PubMed2004

New cytotoxic and molecular-targeted therapies of head and neck tumors.

PURPOSE OF REVIEW: The purpose of this review is to provide an update on novel medical treatments for head and neck cancer. RECENT FINDINGS: Despite the continuing introduction of new cytotoxic agents, such as antimetabolites (capecitabine, pemetrexed), and topoisomerase I inhibitors, the management of advanced head and neck cancer remains challenging. Epidermal growth factor receptor is an appealing target for novel therapies in head and neck cancer. Several rational approaches have been designed to abrogate epidermal growth factor receptor function, among which the development of small molecules, such as gefitinib or erlotinib, that inhibit tyrosine kinase activity, therefore abrogating the receptor's catalytic activity, autophosphorylation, and its engagement with signal transducers. The development of monoclonal antibodies, such as cetuximab, directed against the receptor's extracellular domain and competing for the binding of receptor ligands is another antireceptor strategy, because it induces epidermal growth factor receptor downregulation from the tumor cell surface. Gefitinib has been evaluated in a phase II study in head and neck cancer, at a dose of 500 mg/day. In this study, a 53% disease control rate was achieved, with a low toxicity. Currently, a phase II study at a dose of 250 mg/day is ongoing. A phase II study of erlotinib in advanced head and neck cancer has provided similar results to those of gefitinib, with a 46% control rate and an acceptable toxicity. Phase I studies of cetuximab have been carried out in advanced head and neck cancer, mainly combining the drug with chemotherapy or radiotherapy. Three phase II studies have evaluated the combination of cetuximab with platinum-based chemotherapy in pretreated patients with recurrent/metastatic head and neck cancer, with a control rate ranging from 29 to 66%. A phase III placebo-controlled trial has shown that the addition of cetuximab to cisplatin does not significantly improve median progression-free survival, despite a difference in the response rate between the two arms. Other molecular-targeted approaches in head and neck cancer include farnesyl transferase inhibitors, cell cycle regulators, and gene therapy. SUMMARY: Novel targeted therapies are highly appealing in advanced head and neck cancer, and the most clever way to use them is a matter of intense investigation.

Alkyl and Aryl Transferases↗
PubMed2005

Advances in the diagnosis, evaluation, and management of malignant pleural mesothelioma.

Malignant mesothelioma is an insidious neoplasm arising from the mesothelial surfaces of the pleural and peritoneal cavities, the pericardium, or the tunica vaginalis. A total of 80% of all cases are pleural in origin. The predominant cause of malignant mesothelioma is inhalational exposure to asbestos, although evidence is increasing to support the hypothesis that simian virus-40 virus plays a role in cocarcinogenesis. Immunohistochemical markers such as calretinin, WT-1, and cytokeratin 5/6 are becoming established diagnostic markers. Preliminary data suggests that a soluble form of mesothelin could serve as a serum marker for established and early cases of mesothelioma. Positron emission tomography with 18-fluorodeoxyglucose in conjunction with computed tomograhy scanning has improved preoperative imaging and staging. Prognostic factors have been identified and verified. Negative indicators include thrombocytosis, high leukocyte counts, poor performance status, and nonepithelial histology. For the first time, there is now evidence that some treatments are increasing the quality and quantity of life for patients with mesothelioma. Chemotherapy, with the new multi-targeted antifolate drug Pemetrexed, combined with cisplatin, has shown superior survival rates in a large phase III trial when compared to cisplatin alone. High-dose intensity-modulated radiotherapy when administered after extrapleural pneumonectomy has resulted in excellent local control. Multimodality treatment programs that combine surgical cytoreduction with novel forms of radiation therapy and more effective chemotherapy combinations may offer significant increases in survival for certain subgroups of mesothelioma patients. Innovative palliative approaches have proved successful in alleviation of the significant symptoms experienced by many mesothelioma patients. Experimental treatments such as immunotherapy and gene therapy present a window of hope for all mesothelioma patients, and in the future, may be combined with 'standard therapy' in multimodality protocols. Patients with adequate performance status should be enrolled into clinical trials where possible. Over the past decade, significant advances have been made on several fronts that have improved the ability to diagnose a stage, define prognosis, and treat malignant pleural mesothelioma.

Combined Modality Therapy↗
PubMed2004

Characterization of binding of folates and antifolates to brush-border membrane vesicles isolated from human kidney.

Antifolates such as methotrexate, raltitrexed, and pemetrexed are among the most effective and widely used anticancer drugs. The antifolates are also among the most unpredictable of anticancer drugs with respect to pharmacokinetics and toxicity. In this study, we assessed the binding of folates and antifolates to the folate receptors (FRs) of human proximal tubules and the effects of pH on binding. Binding of [(3)H]folic acid was pH-dependent, with maximal binding seen at pH 6. Equilibrium binding experiments with [(3)H]folic acid showed that K(d) values were unaffected, and B(max) values increased as the pH was decreased from 8.0 to 6.0. Increasing the osmolarity at pH 6.0 had no effect on intravesicular content, confirming that increased site-specific binding caused the observed changes in B(max) values. Enzymatic cleavage of glycosyl-phosphatidylinositol linkages abolished binding of [(3)H]folic acid to brush-border membrane vesicles, suggesting that [(3)H]folic acid was bound to FRs. In concentration-effect experiments conducted at different pH values, the antifolates raltitrexed and (2S)-2-[o-fluoro-p-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl-methyl)-N-(prop-2-ynyl)amino]benzamido]-4-(tetrazol-5-yl) butyric acid (ZD9331) bound more tightly as pH increased from 6.0 to 8.0, whereas binding of 10-propargyl-5,8-dideazafolic acid (CB3717) was unchanged. The results obtained when K(i) values were converted to binding energies suggested that binding of some, but not all, antifolates and folates to FRs was pH-dependent, further indicating roles of luminal pH in renal reabsorption or secretion processes.

Cell Membrane↗
PubMed2025

Artificial intelligence-powered spatial analysis of tumor microenvironment in patients with non-small cell lung cancer with acquired resistance to EGFR tyrosine kinase inhibitor.

PURPOSE: This study evaluated the dynamic changes in the tumor microenvironment (TME) in patients with non-small cell lung cancer (NSCLC) and acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) using an artificial intelligence (AI)-powered spatial TME analyzer. We then assessed the predictive efficacy of immune-checkpoint inhibitors (ICIs)-based treatment. EXPERIMENTAL DESIGN: An AI-powered whole-slide image analyzer was used to segment cancer areas (CAs) and cancer stroma and to identify tumor-infiltrating lymphocytes (TILs), tertiary lymphoid structures, fibroblasts, and endothelial cells (ECs) in the tumor tissue. We analyzed 143 NSCLC samples after resistance to EGFR-TKIs from two cohorts: (1) 89 patients treated with ICI monotherapy and (2) 54 patients from the ATTLAS phase III trial comparing atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP) versus pemetrexed plus carboplatin. RESULTS: Post-TKI samples showed reduced TILs in the CA (p=0.045) and increased ECs in the CA (p=0.005) compared with pre-TKI samples. These changes differed according to EGFR mutation subtype. Higher TILs in CA were associated with a better overall response rate (ORR) and progression-free survival (PFS). Similarly, higher EC levels in CA correlated with improved ORR and PFS. In the ATTLAS cohort, these factors were associated with clinical benefits from ABCP, with a significant association with TILs and a marginal association with ECs. CONCLUSION: Our findings suggest that EGFR-TKIs affect the immune landscape of patients with EGFR-mutated NSCLC. Higher TILs or ECs in the CA were significantly associated with a favorable response to subsequent ICI-based treatment. TRIAL REGISTRATION NUMBER: NCT03991403.

Aged↗
PubMed2005

Human splicing factor SPF45 (RBM17) confers broad multidrug resistance to anticancer drugs when overexpressed--a phenotype partially reversed by selective estrogen receptor modulators.

The splicing factor SPF45 (RBM17) is frequently overexpressed in many solid tumors, and stable expression in HeLa cells confers resistance to doxorubicin and vincristine. In this study, we characterized stable transfectants of A2780 ovarian carcinoma cells. In a 3-day cytotoxicity assay, human SPF45 overexpression conferred 3- to 21-fold resistance to carboplatin, vinorelbine, doxorubicin, etoposide, mitoxantrone, and vincristine. In addition, resistance to gemcitabine and pemetrexed was observed at the highest drug concentrations tested. Knockdown of SPF45 in parental A2780 cells using a hammerhead ribozyme sensitized A2780 cells to etoposide by approximately 5-fold relative to a catalytically inactive ribozyme control and untransfected cells, suggesting a role for SPF45 in intrinsic resistance to some drugs. A2780-SPF45 cells accumulated similar levels of doxorubicin as vector-transfected and parental A2780 cells, indicating that drug resistance is not due to differences in drug accumulation. Efforts to identify small molecules that could block SPF45-mediated drug resistance revealed that the selective estrogen receptor (ER) modulators tamoxifen and LY117018 (a raloxifene analogue) partially reversed SPF45-mediated drug resistance to mitoxantrone in A2780-SPF45 cells from 21-fold to 8- and 5-fold, respectively, but did not significantly affect the mitoxantrone sensitivity of vector control cells. Quantitative PCR showed that ERbeta but not ERalpha was expressed in A2780 transfectants. Coimmunoprecipitation experiments suggest that SPF45 and ERbeta physically interact in vivo. Thus, SPF45-mediated drug resistance in A2780 cells may result in part from effects of SPF45 on the transcription or alternate splicing of ERbeta-regulated genes.

Antineoplastic Agents↗
PubMed2006

Phase II trial of cetuximab in patients with previously treated non-small-cell lung cancer.

PURPOSE: To determine the efficacy of cetuximab in patients with recurrent or progressive non-small-cell lung cancer (NSCLC) after receiving at least one prior chemotherapy regimen. PATIENTS AND METHODS: This was an open-label, phase II study of patients with epidermal growth factor receptor (EGFR) -positive and EGFR-negative advanced NSCLC with Eastern Cooperative Oncology Group performance status 0 to 1. Patients received cetuximab 400 mg/m2 intravenously (IV) during 120 minutes on week 1 followed by weekly doses of cetuximab 250 mg/m2 IV during 60 minutes. A cycle was considered as 4 weeks of treatment and therapy was continued until disease progression or intolerable toxicities. The primary end point was to assess response rate. Secondary end points included an estimation of time to progression and survival. RESULTS: Patient and disease characteristics (n = 66) included EGFR-positive status (n = 60); EGFR-negative status (n = 6); number of prior regimens (one, n = 28; two, n = 27; > or = three, n = 11); male (n = 41); female (n = 25); adenocarcinoma (n = 36); and smoking status (never, n = 13; former, n = 45; current, n = 8). Grade 3/4 toxicities included acne-like rash (6.1%), anaphylactic reactions (1.5%), and diarrhea (1.5%). The response rate for all patients (n = 66) was 4.5% (95% CI, 0.9% to 12.7%) and the stable disease rate was 30.3% (95% CI, 19.6% to 42.9%). The response rate for patients with EGFR-positive tumors (n = 60) was 5% (95% CI, 1.0% to 13.9%). The median time to progression for all patients was 2.3 months (95% CI, 2.1 to 2.6 months) and median survival time was 8.9 months (95% CI, 6.2 to 12.6 months). CONCLUSION: Although the response rate with single-agent cetuximab in this heavily pretreated patient population with advanced NSCLC was only 4.5%, the disease control rates and overall survival seem comparable to that of pemetrexed, docetaxel, and erlotinib in similar groups of patients.

Adult↗
PubMed2002

Pharmacogenomic strategies for developing customized chemotherapy in non-small cell lung cancer.

In this review, we deal with six groups of cytotoxic drugs commonly used in the treatment of non-small cell lung cancer (NSCLC). Although there are many reviews of thymidylate synthase (TS) and antifolate inhibitors, in this article, we have tried to highlight aspects that are more important for medical oncologists to consider when treating NSCLC patients. There is compelling evidence that TS gene transcripts and TS polymorphisms could be used to decide which patients can best benefit from adjuvant chemotherapy approaches, especially in colorectal cancer, and not less importantly, to tailor chemotherapy in metastatic NSCLC when using drugs akin to fluorouracil, such as pemetrexed. Secondly, cisplatin is central to chemotherapy combinations and evidence indicates that DNA repair capacity influences response to cisplatin-based regimens. ERCC1 gene transcript stands out as a predictive marker of cisplatin sensitivity. Thirdly, preliminary studies indicate that upregulation of beta-tubulin III correlates with response to paclitaxel and vinorelbine. Fourthly, overexpression of ribonucleotide reductase can influence response to gemcitabine. Fifthly, we describe mechanisms of resistance to topoisomerase I inhibitors, although this subject has not yet been completely elucidated. Finally, to understand the mechanisms of resistance to EGF-R inhibitors, which have been shown to be useful in many different types of cancer, the Src-STAT signaling pathways are described here in detail. Hopefully, the assessment of Src and of STAT-3 can be implemented as predictive markers.

Animals↗
PubMed2005

How today's developments in the treatment of non-small cell lung cancer will change tomorrow's standards of care.

Cisplatin (Platinol; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and carboplatin (Paraplatin; Bristol-Myers Squibb), together with newer chemotherapies, such as docetaxel (Taxotere; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com), paclitaxel (Taxol; Bristol-Myers Squibb), vinorelbine (Navelbine; GlaxoSmith-Kline, Philadelphia, http://www.gsk.com), pemetrexed (Alimta; Eli Lilly and Company, Indianapolis, http://www.lilly.com), and gemcitabine (Gemzar; Eli Lilly and Company), have improved treatment outcomes in both advanced non-small cell lung cancer (NSCLC) and in the adjuvant/neoadjuvant setting. Newer systemic treatments for NSCLC, used in advanced stage IV management, are beginning to be studied in earlier stages of the disease, when treatment is better tolerated and potentially curative. Hopefully, newer agents with proven efficacies in advanced disease will enhance curability. Following the successful addition of bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA, http://www.gene.com) to carboplatin/paclitaxel in advanced disease, bevacizumab is now being incorporated into adjuvant and neoadjuvant trials. Trials in stage IB-IIIA patients will study neoadjuvant docetaxel/cisplatin/bevacizumab. The discovery that patients with exon 19 and 21 mutations in the epidermal growth factor receptor gene EGFR have around an 80% response rate to gefitinib (Iressa; AstraZeneca Pharmaceuticals, Wilmington, DE, http:// www.astrazeneca-us.com) and that this response confers survival benefit indicates its potential utility for mutation-positive patients with advanced- and earlier-stage disease. Clinical characteristics, such as never smoking status and adenocarcinoma, and especially bronchioloalveolar carcinoma histological features, can also identify individuals likely to respond to EGFR tyrosine kinase inhibitors. Studies of neoadjuvant erlotinib (Tarceva; OSI Pharmaceuticals, Inc., Melville, NY, http://www.osip.com) in operable NSCLC are planned. One such study includes cisplatin and docetaxel. Effective development of active agents and disease management based on molecular profiling of lung tumors will change tomorrow's standard of care.

Antibodies, Monoclonal↗
PubMed2002

Single-agent capecitabine: a reference treatment for taxane-pretreated metastatic breast cancer?

The treatment of patients with metastatic breast cancer that has progressed despite previous anthracycline- and taxane-based therapy is a challenge for oncologists. Several agents, including vinorelbine, gemcitabine, pemetrexed, and particularly capecitabine, have been evaluated in this setting, either alone or in combination with other cytotoxic agents. The efficacy of many of these agents has not yet been clearly established in this setting, as the majority have been evaluated in a limited number of patients and predominantly in single-center trials. Furthermore, some agents with clinically meaningful activity are often associated with significant toxicity, particularly myelosuppression and neuropathy, while less toxic agents/regimens often exchange improved tolerability for reduced activity. Capecitabine, an oral chemotherapeutic, is the agent that has been evaluated most extensively in this setting. A large, phase II trial (n = 163) conducted in North America demonstrated a disease control rate of 63%, including an objective response rate of 20%, median time to disease progression of 3.0 months, and median survival of approximately 1 year. Adverse events were typically mild to moderate in intensity and could be controlled with treatment interruption or, if necessary, dose adjustment to each individual's tolerable dose. Data recently reported from three other large trials in taxane-pretreated patients have revealed similar efficacy and tolerability. Together, these four trials show that single-agent capecitabine, in a population of 500 patients, consistently produced clinically meaningful efficacy, including median survival of approximately 1 year, with a favorable safety profile. Myelosuppression and alopecia were particularly rare. In addition, the oral administration of capecitabine, which enables convenient, patient-oriented therapy, makes it an attractive treatment for patients. Based primarily on the results of the pivotal trial, capecitabine received regulatory approval as treatment for anthracycline- and taxane-pretreated (paclitaxel-pretreated in the U.S.) metastatic breast cancer. In light of the confirmatory results of subsequent large trials, capecitabine is now considered a reference treatment in this setting, as no other agent has consistently demonstrated such high efficacy in as large a patient population.

Administration, Oral↗
PubMed2004

Highlights from the Tenth World Conference on Lung Cancer.

Should adjuvant chemotherapy for resected non-small cell lung cancer (NSCLC) be the standard of care? That question has been much debated since the presentation of results from the International Adjuvant Lung Cancer Trial (IALT) in May 2003 at the plenary session of the American Society of Clinical Oncology annual meeting. The IALT study showed a statistically significant survival advantage for patients treated with cisplatin-based adjuvant chemotherapy. The topic of adjuvant chemotherapy permeated the Tenth World Conference on Lung Cancer held from August 10-14, 2003 in Vancouver, Canada. Updated results of the IALT study were presented along with results from the Big Lung Trial from the United Kingdom and the Adjuvant Lung Project Italy trial, neither of which showed a significant survival benefit for adjuvant chemotherapy. How to put the IALT data into practice remains controversial, and leading lung cancer experts have not reached a consensus. Platinum-based doublets that include a taxane, vinorelbine, or gemcitabine remain the standard of care for the first-line treatment of metastatic NSCLC. However, there may soon be a new option for second-line treatment. A randomized study of pemetrexed in the second-line setting found efficacy similar to that of docetaxel given every 3 weeks, with less toxicity. Gefitinib was recently approved by the U.S. Food and Drug Administration for the treatment of advanced NSCLC following platinum-based chemotherapy and docetaxel. However, concerns have arisen about toxicity due to reports of interstitial pneumonitis from Japan. The observed incidence of interstitial pneumonitis from the data available to date is approximately 1%. Which patients derive the most benefit from gefitinib? It appears that lifetime nonsmokers and patients with bronchioloalveolar histology have the highest probability of disease response.

Antineoplastic Agents↗
PubMed2004

New chemotherapeutic advances in pancreatic, colorectal, and gastric cancers.

Pancreatic, gastric, and colorectal cancers are major causes of morbidity and mortality worldwide. When curative surgical resection is not an option, these malignancies tend to respond very poorly to chemotherapy and carry a dismal prognosis. There is, therefore, an urgent need for novel treatment strategies for these cancers. Great strides have been made in colon cancer treatment with the recent introduction of several novel agents, including capecitabine, irinotecan, and oxaliplatin either alone or in combination regimens. Treatment of advanced colon cancer, however, remains essentially palliative, and treatment-related toxicity remains a significant problem. The treatment of advanced gastric and pancreatic cancer has also seen the introduction of new agents, such as gemcitabine and irinotecan; however, the impact of these agents on survival has been small, and toxicity continues to be a major obstacle. The search for new chemotherapeutic agents and treatment strategies will need to focus on improving outcomes and safety and tolerability profiles. To date, several new agents have shown promise, including pemetrexed, G17DT, bevacizumab, and other targeted agents. Further research into their optimal use either alone or in combination regimens should be a priority.

Antineoplastic Agents↗
PubMed2000

Differences in the induction of DNA damage, cell cycle arrest, and cell death by 5-fluorouracil and antifolates.

Thymidylate synthase (TS) is an important target for chemotherapy and can be inhibited by 5-fluorouracil (5-FU) and the antifolates, AG337 (Nolatrexed) and multitargeted antifolate (MTA or Pemetrexed). In addition, 5-FU can be incorporated into RNA and DNA, and MTA can inhibit two other enzymes. It is, however, unclear to what extent these differences in drug action will influence activation of downstream mechanisms mediated via TS inhibition. Therefore, two human colon cancer cell lines, WiDr and Lovo, with a different clonogenic origin, were treated with equitoxic concentrations of 5-FU, AG337, and MTA to determine the induction of DNA damage, cell cycle arrest, downstream protein expression, and cell death. At these concentrations, the specific TS inhibitor AG337 induced more DNA damage (up to 20%) than MTA and 5-FU. FACS analysis showed that all drugs induced S phase arrest in Lovo and WiDr that was most pronounced after 5-FU and AG337 exposure (50-70%). Western blotting showed that p53 induction was not detectable in mutant (mt) p53 WiDr and increased much earlier in wild-type (wt) Lovo cells after 5-FU and MTA (24 h) than after AG337 exposure (72 h). In contrast to 5-FU-treated Lovo cells, the bcl-2/bax ratio decreased after antifolate exposure. Nevertheless, both 5-FU and antifolates induced similar amounts of cell death (up to 60%). These results demonstrate that in human colon cancer cells differences in downstream events between AG337 and 5-FU or MTA are related to the additional effects of 5-FU and MTA, which are not associated with TS inhibition.

Antimetabolites, Antineoplastic↗