ERCC1 gene polymorphism as a predictor for clinical outcome in advanced colorectal cancer patients treated with platinum-based chemotherapy.

Excision repair cross-complementation group 1 (ERCC1) is a highly conserved protein and an essential member of the nucleotide excision repair pathway. DNA repair is an important mechanism for resistance to platinum-based chemotherapy. Previous studies have shown that ERCC1 gene expression is associated with clinical outcome to platinum chemotherapy in a variety of cancers.

Gene polymorphisms of epidermal growth factor receptor and its downstream effector, interleukin-8, predict oxaliplatin efficacy in patients with advanced colorectal cancer.

Background: Researchers have recently reported an association between the epidermal growth factor receptor (EGFR) pathway and platinum-chemotherapy sensitivity in cancer patients. The (CA)(n) repeat polymorphism in intron 1 of the EGFR gene has been identified and found to alter EGFR expression in vitro as well as in vivo. A higher number of these CA repeats is associated with lower EGFR levels, whereas a low number of repeats is associated with higher EGFR levels.

Assessment of infusional 5-fluorouracil schedule and dose intensity: a Southwest Oncology Group and Eastern Cooperative Oncology Group study.

Background: Building on results from Southwest Oncology Group trial 8905, this trial was designed to compare low-dose continuous infusion (LDCI) of 5-fluorouracil (5-FU) versus intermittent high-dose infusion (HDI) of 5-FU in disseminated colorectal cancer (CRC) for evidence of survival advantage based on dose intensity. A companion trial was funded to assess molecular parameters associated with fluoropyrimidine response or resistance and toxicity from these treatments.

Patients And Methods: Eligibility included histologic diagnosis of disseminated CRC, measurable or evaluable disease, no previous therapy for metastatic disease, performance status of 0-2, and adequate renal, hepatic, cardiac, and hematologic function.

Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors.

Purpose: BAY 43-9006, a novel multikinase inhibitor, prevents tumor growth by combining two antitumor activities: inhibition of both tumor cell proliferation and tumor angiogenesis. This phase I, open-label, nonrandomized, noncontrolled, single-arm, dose escalation study was done to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, effect on biomarkers, and tumor response with BAY 43-9006 in 19 patients with advanced, refractory solid tumors.

Experimental Design: BAY 43-9006 was given orally in repeated cycles of 1-week on/1-week off.

Antiangiogenic agents in cancer therapy.

There is substantial preclinical and clinical evidence that angiogenesis plays a role in the development of tumors and the progression of malignancies. Inhibiting angiogenesis has been shown to suppress tumor growth and metastasis in many preclinical models. These benefits have translated to the clinic with both marketed and investigational antiangiogenesis agents.

Molecular determinants of cetuximab efficacy.

Purpose: To investigate whether mRNA expression levels of cyclin D1 (CCND1), cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), interleukin 8 (IL-8), and vascular endothelial growth factor (VEGF), all members of the EGFR signaling pathway, are associated with clinical outcome in patients with EGFR-expressing metastatic colorectal cancer (CRC) treated with cetuximab.

Patients And Methods: Thirty-nine patients with metastatic CRC, refractory to both irinotecan and oxaliplatin, were enrolled on IMCL-0144 and treated with single-agent cetuximab. The intratumoral mRNA levels of CCND1, Cox-2, EGFR, IL-8, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture microdissection and quantitative real-time polymerase chain reaction.

Epidermal growth factor receptor as a target for chemotherapy.

The epidermal growth factor receptor (EGFR) is overexpressed in as many as 77% of colorectal cancer (CRC) cases. The EGFR is known to be involved in carcinogenetic processes such as cell proliferation, apoptosis, angiogenesis, cell motility, and metastasis. Preclinical and clinical studies have shown that targeting EGFR is a valid strategy for anticancer therapy.

Phase I clinical and pharmacokinetic trial of docetaxel and irinotecan administered on a weekly schedule.

Background: Docetaxel and irinotecan are synergistic agents with a broad spectrum of activity but overlapping myelosuppression. The study was designed to maintain dose intensity while limiting myelosuppression. The objectives of this study were to determine the maximal tolerated dose (MTD) of the combination of docetaxel and irinotecan administered weekly for four consecutive weeks every 42 days, to describe toxicities of this regimen, and to perform a pharmacokinetic analysis to evaluate changes in drug disposition as a function of dose as well as repeated dosing.

Phase II clinical trial of capecitabine in ovarian carcinoma recurrent 6-12 months after completion of primary chemotherapy, with exploratory TS, DPD, and TP correlates: a Gynecologic Oncology Group study.

Purpose: A phase II trial was conducted to evaluate the anti-tumor activity and adverse effects of capecitabine in women with measurable platinum-sensitive ovarian cancer or platinum-sensitive primary peritoneal cancer and to explore the ability of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) to predict response and toxicities.

Experimental Design: Patients were treated with a daily starting dose of 2500 mg/m2/day (divided in two doses given every 12 h) for 14 days of each 21-day cycle. Genotyping in the 5' and 3' ends of TS was performed in DNA from 23/23 pre-treatment blood specimens.

Intermittent dosing of the farnesyl transferase inhibitor tipifarnib (R115777) in advanced malignant solid tumors: a phase I California Cancer Consortium Trial.

Tipifarnib (R115777) inhibits farnesylation of key proteins that modulate signaling pathways implicated in cell growth and proliferation, including members of the Ras and Rho families. It has broad-spectrum antiproliferative activity in vitro and in vivo. Clinical trials employing a continuous administration schedule have demonstrated dose-limiting neurotoxicity and myelosuppression.

Epidermal growth factor receptor gene polymorphisms predict pelvic recurrence in patients with rectal cancer treated with chemoradiation.

An association between epidermal growth factor receptor (EGFR) signaling pathway and response of cancer cells to ionizing radiation has been reported. Recently, a polymorphic variant in the EGFR gene that leads to an arginine-to-lysine substitution in the extracellular domain at codon 497 within subdomain IV of EGFR has been identified. The variant EGFR (HER-1 497K) may lead to attenuation in ligand binding, growth stimulation, tyrosine kinase activation, and induction of proto-oncogenes myc, fos, and jun.

Angiogenesis inhibitors in the treatment of colorectal cancer.

Angiogenesis is critical for normal and pathologic processes in new blood vessel formation. A recent significant advance in the treatment of metastatic colorectal cancer has occurred by the development of agents targeting key regulatory molecules involved in this process, specifically vascular endothelial growth factor (VEGF). These angiogenesis inhibitors, include bevacizumab (Avastin, Genentech, Inc, South San Francisco, CA), which binds free VEGF.

Capecitabine: the new generation of fluoropyrimidines in colorectal cancer.

Colorectal cancer is the second leading cause of cancer death in the USA and fluoropyrimidines have been the mainstay of treatment for over 40 years. Currently, capecitabine is the only orally available fluoropyrimidine approved for treatment in the USA. As a single agent it has demonstrated activity and equivalence to 5-fluorouracil (5-FU) intravenous administration via the Mayo Clinic regimen, in both the metastatic and adjuvant settings.

Tailored chemotherapy for colorectal cancer: a new approach to therapy.

The treatment of colorectal cancer has advanced over the past several years with the introduction of several active agents. Determining which patients to treat with chemotherapy and choosing optimal treatment would allow practioners to maximize the benefit of chemotherapy. Several prognostic and predictive markers have been identified and include oncogenes, tumor suppressor genes, genes involved in angiogenic and apoptotic pathways and cell proliferation, and those encoding targets of chemotherapy.

Phase II clinical trial of 5-fluorouracil, trimetrexate, and leucovorin (NFL) in patients with advanced pancreatic cancer.

Background: Advanced pancreatic cancer has limited treatment options. 5-fluorouracil (5-FU) is frequently used in the treatment of pancreatic cancer. Preclinical studies suggest synergism between trimetrexate (TMTX),5-FU, and leucovorin (NFL).

Integration of novel agents in the treatment of colorectal cancer.

Two of the most promising new targets in the treatment of colorectal cancer are the epithelial growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF). Agents that inhibit the EGFR or bind to VEGF have demonstrated clinical activity as single agents and in combination with chemotherapy in phase II and phase III clinical trials. The most promising of these agents are cetuximab, which blocks the binding of EGF and transforming growth factor alpha (TGF-alpha) to EGFR, and bevacizumab, which binds free VEGF.

Mutant DNA in plasma of lung cancer patients: potential for monitoring response to therapy.

The hypothesis tested was that mutant tumor DNA shed into plasma would show predictive value for monitoring response to therapy in non-small cell lung carcinoma patients. Pretreatment plasma specimens from 25 patients on a phase I trial were evaluated, 12 with paired posttreatment specimens, and 138 patients on the Southwest Oncology Group S0003 trial, 38 with paired posttreatment specimens, for the presence of K-RAS mutations. Thirteen tumor specimens from the phase I trial patients and seven tumor specimens from S0003 patients were also available for comparative analysis of K-RAS mutations in tumor tissue and plasma.

The role of proteasome inhibitors in solid tumors.

The proteasome is a multicatalytic protein complex whose principal task is the degradation of a large array of proteins within the cell. Its substrates include proteins involved in cell cycle regulation, tumor suppression, apoptosis, transcription, and angiogenesis, among others. This makes the inhibition of the proteasome a promising novel therapeutic approach to cancer treatment.

A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels.

Objective: A 6 bp deletion polymorphism in the thymidylate synthase (TS) gene was investigated in order to determine its function.

Methods: A luciferase system was used to investigate the function of the 6 bp/1494 polymorphism in vitro. A group of 43 patients with colorectal carcinoma were evaluated for the 6 bp/1494 polymorphism and for intratumoral TS mRNA levels in vivo.

Pharmacogenetic aspects in treatment of colorectal cancer--an update.

Pharmacogenomic analyses will become crucial to predict patients' toxicity to treatment and will also help to predict the tumor response. Processes of drug metabolism, drug efflux, DNA-repair and characteristics of drug targets are critical checkpoints of drug efficacy. These crucial pathways for drug action have been part of pharmacogenomic studies evaluating the impact of genomic variants on transcription, translation, protein structure and substrate binding of the genes involved.