Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Capecitabine (Xeloda) is a new, orally administered, enzyme-activated fluoropyrimidine carbamate designed to generate high levels of fluorouracil (5-FU) in tumor cells. Selective tumor activation of 5'-deoxy-5-fluorouridine, the last enzymatic step of a three-enzyme process, is catalyzed by thymidine phosphorylase, a tumor-associated angiogenic growth factor. Since levels of thymidine phosphorylase are often higher in tumors than in surrounding normal tissues, this stepwise process provides tumor selectivity and potentially decreases toxicity to normal tissues. Preclinical studies show that capecitabine has significant activity against a variety of tumor types when used as monotherapy and in combination with other chemotherapeutic agents. Capecitabine is currently approved for the treatment of patients with metastatic breast cancer resistant to paclitaxel (Taxol) and in whom further anthracycline therapy is contraindicated. It has demonstrated efficacy in patients with advanced colorectal carcinoma, and studies are ongoing in other tumor types.
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PMID:Pharmacology and clinical status of capecitabine. 1103 28

Two patients with liver metastasis from gastric cancer who responded remarkably to a combined therapy of 5'-DFUR and PSK are reported. The first patient had liver metastases 8 months postoperatively. Her AFP level was 513 ng/ml and CEA was 30 ng/ml. After the combined therapy, all liver metastases showed a calcified change. Tumor markers of AFP and CEA decreased remarkably to the normal level within 3 weeks after the therapy. The patient had no relapse as of December 1999. The second patient with liver metastases was treated using the same combined therapy for 14 days preoperatively. The size of liver metastases had decreased remarkably by the time of the operation. A small metastasis of S8 (0.5 x 0.5 cm) was resected. No other liver metastasis was detected by intraoperative ultrasonography. The patient had no relapse as of February 2000. It is reported that PSK produces several cytokines which induce thymidine phosphorylase expression. The present report suggests that the upregulation of PyNPase might enhance the antitumor effect of 5'-DFUR.
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PMID:[Two patients with liver metastasis from gastric cancer who responded remarkably to combined therapy of 5'-DFUR and PSK]. 1105 26

The assessment of the angiogenic profile of tumors may become an important tool as a guide for the inclusion of novel drugs and molecular therapies into the standard chemoradiotherapy policy. Several studies have shown the prognostic importance of microvessel density (MVD) and of angiogenic factor expression in operable gastric cancer. In the present study we investigated, with immunohistochemistry the MVD, the expression of vascular endothelial growth factor (VEGF) and of thymidine phosphorylase (TP) expression, as well as the nuclear expression of p53 protein, in a series of patients with locally advanced inoperable gastric cancer. A strong association of VEGF with TP expression was noted (P = 0.005), and tumors coexpressing these factors had a statistically higher MVD (P = 0.0001). Nuclear p53 accumulation was also related to a high MVD (P = 0.004), and this was independent of VEGF or TP expression. Microvessel density showed a bell-shaped association with prognosis; cases with an intermediate MVD exhibit a favorable outcome (P < 0.05). A trend of nuclear TP expression to define a group of patients with poorer prognosis was noted (P = 0.06), while none of the remaining variables showed any significant association. The immunostaining results allowed the grouping of the angiogenic profile in four major categories: 1) highly vascularized tumors with VEGF and/or TP expression (about 36% of cases); 2) highly angiogenic tumors with p53 nuclear accumulation and low VEGF/TP expression (7% of cases); 3) poorly vascularized tumor with low VEGF/TP and negative nuclear p53 staining (32% of cases); 4) poorly vascularized tumors with TP expression (7% of cases). Specific therapies targeting hypoxia, VEGF, or TP expression as well as p53 gene therapy have entered clinical experimentation or are already available for clinical use. Using the suggested markers more than 80% of locally advanced gastric carcinomas can be grouped in different categories according to their angiogenic profile. Such a categorization may be useful for phase III trials on novel therapies targeting the major angiogenesis-related features studied here.
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PMID:Angiogenic interactions of vascular endothelial growth factor, of thymidine phosphorylase, and of p53 protein expression in locally advanced gastric cancer. 1106 44

Growth and metastatic spread of invasive carcinoma depends on angiogenesis, the formation of new blood vessels. Platelet-derived endothelial cell growth factor (PD-ECGF) is an angiogenic growth factor for a number of solid tumors, including lung, bladder, colorectal, and renal cell cancer. Cervical intraepithelial neoplasia (CIN) is the precursor to squamous cell cervical carcinoma (SCC). Mean vessel density (MVD) increases from normal cervical tissue, through low- and high-grade CIN to SCC. We evaluated PD-ECGF immunoreactivity and correlated its expression with MVD in normal, premalignant, and malignant cervical tissue. PD-ECGF expression was assessed visually within the epithelial tissues and scored on the extent and intensity of staining. MVD was calculated by counting the number of vessels positive for von Willebrand factor per unit area subtending normal or CIN epithelium or within tumor hotspots for SCC. Cytoplasmic and/or nuclear PD-ECGF immunoreactivity was seen in normal epithelium. PD-ECGF expression significantly increased with histologic grade from normal, through low- and high-grade CIN, to SCC (P < .02). A progressive significant increase in the microvessel density was also seen, ranging from a mean of 28 vessels for normal tissue to 57 for SCC (P < .0005). No correlation was found between PD-ECGF expression and MVD (P = .45). We conclude that PD-ECGF expression and MVD increase as the cervix transforms from a normal to a malignant phenotype. PD-ECGF is thymidine phosphorylase, a key enzyme in the activation of fluoropyrimidines, including 5-fluorouracil. Evaluation of PD-ECGF thymidine phosphorylase expression may be important in designing future chemotherapeutic trials in cervical cancer.
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PMID:Platelet-derived endothelial cell growth factor expression and angiogenesis in cervical intraepithelial neoplasia and squamous cell carcinoma of the cervix. 1107 33

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel fluoropyrimidine carbamate, which was designed to be sequentially converted to 5-fluorouracil (5-FU) by three enzymes located in the liver and in tumors; the final step is the conversion of 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-FU by thymidine phosphorylase (dThdPase) in tumors. In human cancer xenograft models, capecitabine given orally yielded substantially higher concentrations of 5-FU within tumors than in plasma or normal tissue (muscle). The tumor 5-FU levels were also much higher than those achieved by intravenous administration of 5-FU at equitoxic doses. Capecitabine and its intermediates are not cytotoxic by themselves, but become effective after their conversion to 5-FU. This tumor selective delivery of 5-FU ensured greater efficacy and a more favorable safety profile than with other fluoropyrimidines. In 24 human cancer xenograft models studied, capecitabine was more effective at a wider dose range and had a broader spectrum of antitumor activity than 5-FU, UFT or its intermediate metabolite 5'-DFUR. The susceptibility of the xenografts to capecitabine correlated with tumor dThdPase levels. Moreover, the conversion of 5'-DFUR to 5-FU by dThdPase in tumor was insufficient in a xenograft model refractory to capecitabine. In addition, the efficacy of capecitabine was enhanced by dThdPase up-regulators, such as taxanes and cyclophosphamide. The efficacy of capecitabine may, therefore, be optimized by selecting the most appropriate patient population based on dThdPase status and/or by combining it with dThdPase up-regulators. Capecitabine has additional characteristics not found with 5-FU, such as potent antimetastatic and anticachectic actions in mouse tumor models. With this profile, capecitabine may have substantial potential in cancer treatment.
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PMID:Capecitabine: preclinical pharmacology studies. 1108 70

Drug development has undergone rapid shifts in methodology and the use of rationally derived agents which either target specific tissues or molecules such as receptors or enzymatic sites. Capecitabine is a rationally derived prodrug of 5-fluorouracil which is based upon the known high concentration of the enzyme thymidine phosphorylase in many human tumors. The first prodrug designed to exploit this biochemical finding was 5-DFUR which allowed cytotoxic 5-fluorouracil to be preferentially concentrated in tumors. Unfortunately, in man this agent was associated with significant gastrointestinal toxicity. Further manipulation of this molecular resulted in capecitabine which is a relatively inert prodrug, undergoes three enzymatic steps, and offers the potential of less gastrointestinal toxicity. Phase I trials have examined several schedules with the divided oral daily x 14 schedule every 3 weeks as the preferred phase II and phase III dosing method. This agent demonstrates significant antitumor effect in diseases known to be responsive to fluoropyrimidines. Further study is needed to determine whether capecitabine has a broader spectrum of action thus affecting other tumor types than 5-fluorouracil. Major dose limiting toxicities have been hand foot syndrome, nausea/vomiting, and diarrhea.
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PMID:Capecitabine. 1108 71

Angiogenesis is essential for tumor growth and metastasis. It is regulated by numerous angiogenic factors, one of the most important being vascular endothelial growth factor (VEGF). Recently, VEGF-C, a new VEGF family member, has been identified that binds to the tyrosine kinase receptors flt-4 [VEGF receptor (VEGFR) 3] and KDR (VEGFR2). Although the importance of VEGF has been shown in many human tumor types, the contribution of VEGF-C and its primary receptor flt-4 to tumor progression is less well understood. We have therefore measured the level of VEGF-C, flt-4, and KDR mRNA by RNase protection assay and the pattern of VEGF-C expression by immunohistochemistry in 11 normal breast tissue samples and 61 invasive breast cancers. No significant difference in VEGF-C expression was observed between normal and neoplastic breast tissues (P = 0.11). There was a significant correlation between VEGF-C and both flt-4 (P = 0.02) and KDR (P = 0.0002), but no association was seen between VEGF-C and either lymph node status (P = 0.66) or number of involved nodes (P = 0.88), patient age (P = 0.83), tumor size (P = 0.20), estrogen receptor status (P = 0.67), or tumor grade (P = 0.35). No significant relationship was present between VEGF-C and vascular invasion (P = 0.30), tumor vascularity (P = 0.21), VEGF-A (P = 0.62), or thymidine phosphorylase expression (P = 1.00). VEGF-C was expressed predominantly in the cytoplasm of tumor cells, although occasional stromal components including fibroblasts were also positive. We could demonstrate no association between lymph node metastasis and either VEGF-C (P = 0.66) or flt-4 (P = 0.4). However, we did observe a significant loss of the long but not the short isoform of flt-4 in tumors compared with normal tissues (P = 0.02 and P = 0.25, respectively), and this difference was largely accounted for by the reduction of long flt-4 in node-positive tumors. These findings strongly support a role for VEGF-C/flt-4 signaling in tumor growth by enhancement of angiogenesis and/or lymphangiogenesis and suggest that differential regulation of these processes may be controlled via flt-4 isoform transcription. They further suggest that the measurement of flt-4 isoform expression may identify a patient group that is likely to have node-positive disease and therefore benefit from additional treatment and also emphasize an additional ligand interaction that could be exploited by anti-VEGFR therapy.
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PMID:The short form of the alternatively spliced flt-4 but not its ligand vascular endothelial growth factor C is related to lymph node metastasis in human breast cancers. 1110 44

To clarify biological and clinical significance of tumor angiogenesis in the development of ovarian carcinoma, we investigated the relationship between tumor vascularity, the expression of thymidine phosphorylase (dThdPase), which is an angiogenic factor identical to platelet-derived endothelial cell growth factor (PD-ECGF), and patient outcome in ovarian carcinoma, including serous surface papillary carcinoma (SSPC). Primary tumor specimens (stages I-IV) from 54 patients were examined. Intratumoral microvessel density (IMVD) and dThdPase expression were evaluated immunohistochemically using anti-CD34 and anti-dThdPase antibodies, and results were correlated with clinicopathologic parameters and prognosis. IMVD for the 54 tumors ranged from 22.5 to 120.7 (number/0.73686 mm2/field). Twenty-three tumors were positive, and 31 tumors were negative for dThdPase expression. IMVD positively correlated with the expression of dThdPase (p < 0.01), tumor size, and peritoneal metastases (p < 0.05). However, there was no statistical correlation between IMVD, dThdPase expression, and clinical outcome. Of the 54 patients examined, 30 were diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage III or IV primary ovarian carcinoma, and 9 were diagnosed with SSPC. There were no significant differences between the two groups with respect to clinicopathologic features, IMVD, dThdPase expression, or patient outcome. In conclusion, angiogenic activity may be necessary for the growth of metastatic implants in ovarian carcinoma and SSPC.
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PMID:Tumor angiogenesis and thymidine phosphorylase expression in ovarian carcinomas including serous surface papillary adenocarcinoma of the peritoneum. 1110 65

We measured thymidine phosphorylase activity in colorectal cancer tissue and conducted immunostaining to investigate enzyme expression in the tumor tissue. The results showed a correlation between staining ratio of thymidine phosphorylase and cancer progression as well as a correlation between enzyme activity and staining ratios of cancer cells and stromal cells. Since enzyme activity levels can be judged by staining ratios, this method may be useful for assessing cancer malignancy.
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PMID:The significance of thymidine phosphorylase expression in colorectal cancer. 1111 83

Several studies have supported the hypothesis that adrenocortical tumor formation is the result of a multistep process. The angiogenic switch has been proposed to be a key step in tumor progression from adenoma to carcinoma. In this study we measured the cytosolic concentrations of three proteins involved in angiogenesis [namely platelet-derived endothelial cell growth factor vascular endothelial cell growth factor A (VEGF-A), and thrombospondin-1 (TSP1)] in a series of 43 human sporadic adrenocortical tumors. The tumors were classified as adenomas (n = 18), transitional tumors (n = 12), or carcinomas (n = 13) according to the histological criteria defined by Weiss. Platelet-derived endothelial cell growth factor/thymidine phosphorylase levels were not significantly different among these three groups. One hundred percent of the adenomas and 73% of the transitional tumors showed VEGF-A concentrations under the threshold value of 107 ng/g protein, whereas 75% of the carcinomas had VEGF-A concentrations above this threshold value. Similarly, 89% of the adenomas showed TSP1 concentrations above the threshold value of 57 microg/g protein, whereas only 25% of the carcinomas and 33% of the transitional tumor samples did so. Insulin-like growth factor II overexpression, a common genetic alteration of adrenocortical carcinomas, was significantly correlated with higher VEGF-A and lower TSP1 concentrations. The tumors from the 6 patients with tumor recurrence after surgical ablation showed significantly higher VEGF-A values than the carcinomas and the transitional tumors from patients that did not relapse. Taken together, these data suggest that a decrease in TSP1 expression is an event that precedes an increase in VEGF-A expression during adrenocortical tumor progression. The population of premalignant tumors with low TSP1 and normal VEGF-A levels could represent a selective target for antiangiogenic therapies.
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PMID:Expression of the angiogenesis markers vascular endothelial growth factor-A, thrombospondin-1, and platelet-derived endothelial cell growth factor in human sporadic adrenocortical tumors: correlation with genotypic alterations. 1113 36


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