Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the past decade, there have been several significant advances in the treatment of metastatic colorectal cancer. These include the introduction of the cytotoxic agents capecitabine, irinotecan, and oxaliplatin. Given their diverse mechanisms of action and toxicity profiles, combinations of fluoropyrimidines, irinotecan, and oxaliplatin have proven feasible and have improved patient outcomes compared with 5-fluorouracil alone. Recently, improved understanding of the biology of colorectal cancer has led to the identification of new molecular targets and the development of pharmacologic agents that hold promise for greater tumor selectivity than traditional cytotoxic agents. Two approaches with early indications of clinical activity against colorectal cancer are inhibition of epidermal growth factor receptor signaling and inhibition of the vascular endothelial growth factor pathway. Furthermore, biochemical and genetic profiling of individual tumors, as well as patient genotyping, may ultimately guide clinicians in making rational treatment decisions based on predicted antitumor efficacy or toxicity of selected agents. This article reviews these recent advances in the systemic treatment of colorectal cancer, including discussion of promising agents in clinical development.
Clin Colorectal Cancer 2003 Nov
PMID:Development of new agents for the treatment of advanced colorectal cancer. 1470 74

High preoperative circulating vascular endothelial growth factor (VEGF) is predictive of poor prognosis in patients with colorectal cancer (CRC). However, postoperative circulating VEGF has not yet been evaluated as a prognostic marker in CRC patients. In 318 consecutive patients who had undergone curative resection of primary CRC, the prognostic value of VEGF concentrations in plasma and serum obtained 6 months postoperatively was analysed and the results compared with the prognostic value of postoperative carcinoembryonic antigen (CEA) concentrations in matched serum samples. In univariate analyses, high serum and plasma VEGF ( > 533 pg/ml and > 112 pg/ml, respectively) had no significant (p = 0.17 and p = 0.13, respectively) impact on overall survival. On the contrary, high serum CEA ( > 5 ng/ ml) was significantly (p < 0.0001) correlated to a poor prognosis. Finally, in multivariate analyses, the combination of high serum CEA and high serum VEGF was significantly (hazard ratio 3.0, p = 0.02) associated with poor survival compared to high serum CEA and low serum VEGF. It is concluded that 6 months postoperatively serum CEA is a better prognostic marker than corresponding serum and plasma VEGF. However, high serum VEGF within high serum CEA was an even better predictor of overall survival than high serum CEA alone.
 ...
PMID:Circulating vascular endothelial growth factor six months after primary surgery as a prognostic marker in patients with colorectal cancer. 1496 45

Recent evidence indicates that treatment with a humanized monoclonal antibody (bevacizumab) directed at vascular endothelial growth factor improves response and survival in metastatic colorectal cancer when added to standard chemotherapy, validating angiogenesis as a therapeutic target. Investigators from the Eastern Cooperative Oncology Group (ECOG) have initiated a number of Phase III studies that will help further define the role of antiangiogenic agents for the treatment of breast, colon, lung, renal, and head and neck cancer, as well as melanoma and myeloma. The agents being evaluated target various biological functions involved in angiogenesis, including vascular endothelial growth factor (bevacizumab), endothelial cell proliferation (thalidomide, IFN-alpha), and matrix metalloproteinases (marimastat). These clinical trials include correlative laboratory studies aimed at elucidating how these agents may exert their clinical effects. The portfolio of Eastern Cooperative Oncology Group studies will serve to further define the role of this therapeutic strategy for patients with advanced cancer.
 ...
PMID:Evaluating antiangiogenesis agents in the clinic: the Eastern Cooperative Oncology Group Portfolio of Clinical Trials. 1497 16

Initial studies with angiogenesis inhibitors showed little clinical benefit. However, recently reported clinical studies in colorectal cancer have shown that bevacizumab, a vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with cytotoxic therapy has positive effects on patient survival. Furthermore, the VEGF receptor kinase (VEGF-R) tyrosine kinase inhibitor, vatalanib, has also shown encouraging results in colorectal cancer, with molecular resonance imaging providing evidence that the anti-tumor efficacy was indeed the result of anti-angiogenic activity. Both of these agents are progressing in phase III trials. This proof of concept has stimulated the desire for second-generation VEGF-R inhibitors having an improved profile. Structural biology insight regarding the binding mode of protein kinase inhibitors is valuable for the design of molecules possessing superior selectivity, efficacy and tolerability. Towards this goal, we have developed a new series of VEGF-R2 kinase inhibitors, based upon an anthranilic acid amide scaffold. An X-ray crystal structure of a representative compound, AAL993 (ZK260253), in complex with the catalytic domain of diphosphorylated VEGF-R2 has revealed that this molecule binds to an inactive conformation of the protein. This binding mode, similar to that observed for the anti-leukemia drug, imatinib in complex with c-Abl kinase, may be responsible for the high selectivity of AAL993 and provides valuable insight for the design of further compounds.
 ...
PMID:Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis. 1502 47

Endocrine glands-derived-vascular endothelial growth factor (EG-VEGF) was recently cloned as a new angiogenic factor that selectively acts on the endothelium of endocrine gland cells. We evaluated the involvement of EG-VEGF in colorectal cancer. The expression of EG-VEGF was confirmed in all of the colorectal cancer cell lines. (On the other hand, the expression of EG-VEGF mRNA was not detected in colorectal normal mucosae.) Stable EG-VEGF infectors of colorectal cancer cell line SW620 were produced, EG-VEGF transfectants were implanted into cecum and s.c., and cell proliferation was evaluated. Angiogenesis was evaluated by dorsal air sac method. Liver metastasis was evaluated after the implantation of EG-VEGF transfectants into the mouse spleen. Tumor proliferation (cecum, s.c.) was significantly higher in the EG-VEGF transfectants than in the control cells. The small vessels were significantly increased in EG-VEGF transfectants as compared with those in control cells. Also, liver metastatic ratio was higher in the EG-VEGF transfectants than in the control cells. In this study, EG-VEGF, a new angiogenic factor, may lead to angiogenesis, promoting cell proliferation and liver metastasis in colorectal cancers. When the EG-VEGF gene-overexpressing colorectal cancer cell line that had been treated with phosphorothioate antisense EG-VEGF oligonucleotides was injected s.c. into mice, angiogenesis and tumor growth were inhibited. Although the novel angiogenesis factor EG-VEGF was not expressed in the normal colorectal mucosa, it was expressed in colorectal cancer cells, which indicates that it is a cancer-specific and possibly tissue-specific angiogenesis factor in the large intestine, and which suggests that it can be targeted by a novel antiangiogenesis therapy.
 ...
PMID:Angiogenesis and tumor proliferation/metastasis of human colorectal cancer cell line SW620 transfected with endocrine glands-derived-vascular endothelial growth factor, as a new angiogenic factor. 1502 21

Epidemiological studies show a strong link between postmenopausal hormone replacement therapy and decreased incidence of colorectal cancer. The colon cancer cell line, COLO 205, develops sensitivity to 17beta-oestradiol (E(2)) in apoptosis assays with increasing passage number (>40), and we hypothesised that genes selectively regulated in multiply passaged cells were likely to be important in E(2)-related apoptosis. Gene array analysis was used to compare the patterns of genes up- or down-regulated in E(2)-sensitive and -insensitive cells. For some genes, changes in mRNA expression were confirmed by protein expression analyses. Changes found in response to E(2) in multiply passaged cells, but not minimally passaged cells, included induction of growth arrest and DNA damage-inducible protein 153 (GADD153), and repression of Kirsten-Ras 2B (K-Ras-2B), metastasis inhibition factor NM23 and vascular endothelial growth factor. A second group of genes was regulated with E(2) exposure in both cell types, and is unlikely to be critically involved in E(2)-associated apoptosis. These included up-regulation of butyrate response factor 1 (BRF1) and down-regulation of c-jun and the breast cancer associated ring domain gene known as BARD1. By comparing control arrays from the two cell populations, cAMP-response element-binding protein (CBP), which is associated with steroid receptor-dependent target gene transcription and the oncoprotein, tyrosine kinase-T3 (TRK-T3), were up-regulated whereas retinoic acid receptor alpha (RARalpha) was down-regulated in multiply passaged cells. This study provides evidence for selective regulation of genes in colon cancer cells by E(2), indicates which of those regulated are likely to be involved in induced apoptosis, and suggests genes likely to be responsible for facilitation.
 ...
PMID:Targets of 17beta-oestradiol-induced apoptosis in colon cancer cells: a mechanism for the protective effects of hormone replacement therapy? 1512 81

Cancer chemotherapy in the treatment of colorectal cancer has been evolving so extensively than ever. 5-fluorouracil (5-FU) has been a pivotal and a single active agent in the treatment of colorectal cancer. Reproducing and consistent better response rate has been shown since the introduction of the concept of biochemical modulation of 5-FU by leucovorin, a reduced folate, to the clinic and a combination chemotherapy of 5-FU and leucovorin (FL) has enable us to obtain a response rate around 20-30% and a median survival time ranging from 10 to 12 months. IFL regimen combing CPT-11 with FL showed a better MST ranging from 14 to 15 months, but now serious toxicity precludes general use outside of clinical trials. In the Europe, de Gramont regimen, an unique dose and schedule of 5-FU using a combination of continuous intravenous infusion of 5-FU with leucovorin over two days and bolus infusion of 5-FU twice over the same period, has been developed and shown improved antitumor activity and toxic profiles. FOLFOX 4, a combination chemotherapy of de Gramont regimen and oxaliplatin which is a third generation of cisplatin and a uniqe toxic profile with neuropathy, has demonstrated improved MST over a year and acceptable toxic profiles. Now FOLFOX 4 is considered to be a standard chemotherapy for the patients with advanced colorectal cancer, since a large phase III randomized study has shown that FOLFOX 4 was the most active and less toxic treatment regimen among active regimens such as IFL and IROX (CPT-11 and oxaliplatin). More recently, a combination of IFL and bevacizumab which is one of the molecular target agents and a antibody agent against vascular endothelial growth factor (VEGF), has demonstrated better MST reaching 20 months. Future large scale trials will attempt to develop more active regimen incorporating so-called molecular target agents.
 ...
PMID:[Chemotherapy]. 1517 Sep 77

In colorectal cancer, increased expression of the angiogenesis promoter vascular endothelial growth factor correlates with invasiveness, vascular density, metastases, recurrence and prognosis. Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor. In recent clinical trials, bevacizumab has been shown to prolong the time to disease progression and the survival of patients with colorectal cancer. In six patients with adenocarcinoma of the rectum, bevacizumab decreased tumour blood perfusion and volume, interstitial fluid pressure, the number of circulating endothelial cells and fluorodeoxyglucose uptake. Surgical specimens showed a marked response in all six patients with only microscopic disease in five of the patients. These effects of bevacizumab on the vascular biology of tumours probably underlie the progression and survival benefits observed in clinical trials of colorectal cancer.
 ...
PMID:Vascular biology support for the use of bevacizumab in colorectal cancer. 1517 56

Advanced colorectal cancer remains an urgent health concern, despite improvements in systemic chemotherapy. Targeted therapeutics promise effective tumor therapy with minimal side effects. Angiogenesis (the formation of new blood vessels) is essential for tumor growth and metastasis and may be an ideal target in the search for new antineoplastic agents. Vascular endothelial growth factor is one of the best characterized of the proangiogenic growth factors that regulate angiogenesis and is a logical target in colorectal cancer therapy. Bevacizumab (Avastin; Genentech Inc.; South San Francisco, CA), a humanized murine monoclonal antibody directed at vascular endothelial growth factor, is being evaluated in the treatment of various types of cancer. It has shown promising efficacy in phase II clinical trials in patients with metastatic colorectal cancer. Addition of bevacizumab at a dose of 5 mg/kg to chemotherapy (5-fluorouracil plus leucovorin) resulted in a higher objective response rate (40% versus 17%), longer time to disease progression (9.0 versus 5.2 months), and longer median survival time (21.5 versus 13.8 months). Hypertension and thrombosis were the principal safety concerns, but were manageable. Further phase II/III studies of bevacizumab, administered with 5-fluorouracil plus leucovorin, with or without irinotecan and/or oxaliplatin, in colorectal cancer, are under way.
 ...
PMID:Targeted therapy of colorectal cancer: clinical experience with bevacizumab. 1517 11

Bevacizumab (Avastin; Genentech, Inc.; South San Francisco, CA) is a recombinant, humanized monoclonal antibody to vascular endothelial growth factor, a key regulator of tumor angiogenesis. Bevacizumab demonstrated potent antitumor activity in preclinical models and has also shown biologic activity and clinical benefit in clinical studies. Notably, a randomized, placebo-controlled phase II trial in renal cell carcinoma demonstrated a significantly longer time to tumor progression with bevacizumab monotherapy. Furthermore, in a phase III trial for untreated advanced colorectal cancer, the addition of bevacizumab to chemotherapy led to significantly longer overall survival and progression-free survival times than chemotherapy alone. The clinical development of bevacizumab has been expanded to include confirmatory phase III trials and exploratory phase II trials in a variety of solid tumors and hematologic malignancies. Treatment regimens being examined include bevacizumab alone and in combination with conventional chemotherapy, radiation, immune therapy, and biologically targeted agents.
 ...
PMID:Expanding the clinical development of bevacizumab. 1517 13


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>