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:C0699790 (colon cancer)
28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The positive impact on survival of traditional chemotherapeutic agents has renewed interest in developing newer cytotoxic agents and orally active compounds with improved therapeutic indices. In addition, new insights into the pathways of human tumorigenesis have led to novel approaches aimed at specific mechanism-based targets. The taxane class, of which paclitaxel was the first member, has the unique ability to promote and stabilize microtubule function directly, thereby inhibiting mitotic progression and inducing apoptotic cell death. Paclitaxel provides treatment benefit in a broad range of solid tumors including breast, ovarian, and lung cancer. The success with paclitaxel stimulated interest in the microtubule as a new therapeutic target. Taxane analogues with improved preclinical efficacy have been identified and are entering clinical trials. The enthusiasm for oral anticancer agents and the therapeutic importance of platinum compounds has led to the development of JM216 (satraplatin), a novel platinum IV coordination complex with oral activity in cisplatin-resistant cell lines, which is now in phase III trials in prostate cancer. Another compound in late development is DPPE, a chemopotentiator that enhances the in vivo antitumor effects of cytotoxic agents such as doxorubicin, cyclophosphamide, and cisplatin. Agents that inhibit topoisomerase I and II have also been of interest. TAS-103 is a dual topoisomerase I and II inhibitor with preclinical efficacy in a broad spectrum of tumors and in multidrug-resistant tumor cell lines. Vaccination strategies represent a rational therapeutic approach in the minimal residual disease or high-risk adjuvant therapy setting. The GMK and MGV vaccines utilizing ganglioside antigens overexpressed on human tumors such as melanoma and small cell lung cancer appear to induce antibody production reliably at tolerable doses and are under further clinical investigation. Inhibition of matrix metalloproteinases (MMPs) is another attractive target for intervention in several aspects of tumor progression. Local production of MMPs with subsequent degradation of the extracellular matrix is implicated in supporting tumor growth, invasion, and angiogenesis. The development of orally active, nontoxic MMP inhibitors is critical since these compounds will likely require chronic administration in conjunction with other therapies. Oncogenes and tumor suppressor genes are appealing targets for therapy since they are thought to be responsible for a significant number of cancers. Mutations in the Ras oncogene occur with great frequency in a number of human cancers including lung, pancreas, and colon cancer. Clinical development of potent and selective inhibitors of farnesyltransferase, the Ras-processing enzyme, is ongoing. These compounds uncouple Ras activity, affect tumor growth, and have demonstrated significant antitumor activity against experimental models of human cancer. The exciting compounds and novel therapeutic approaches currently under investigation by Bristol-Myers Squibb Pharmaceutical Research Institute offer great potential as effective cancer chemotherapy agents for the near future.
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PMID:Promising new developments in cancer chemotherapy. 1035 61

Salicylate and its pro-drug form aspirin are widely used medicinally for their analgesic and anti-inflammatory properties, and more recently for their ability to protect against colon cancer and cardiovascular disease. Despite the wide use of salicylate, the mechanisms underlying its biological activities are largely unknown. Recent reports suggest that salicylate may produce some of its effects by modulating the activities of protein kinases. Since we have previously shown that the farnesyltransferase inhibitor l-744, 832 inhibits cell proliferation and p70(s6k) activity, and salicylate inhibits cell proliferation, we examined whether salicylate affects p70(s6k) activity. We find that salicylate potently inhibits p70(s6k) activation and phosphorylation in a p38 MAPK-independent manner. Interestingly, low salicylate concentrations (</=250 microm) inhibit p70(s6k) activation by phorbol myristate acetate, while higher salicylate concentrations (>/=5 mm) are required to block p70(s6k) activation by epidermal growth factor + insulin-like growth factor-1. These data suggest that salicylate may selectively inhibit p70(s6k) activation in response to specific stimuli. Inhibition of p70(s6k) by salicylate occurs within 5 min, is independent of the phosphatidylinositol 3-kinase pathway, and is associated with dephosphorylation of p70(s6k) on its major rapamycin-sensitive site, Thr(389). A rapamycin-resistant mutant of p70(s6k) is resistant to salicylate-induced Thr(389) dephosphorylation.
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PMID:Salicylate-induced growth arrest is associated with inhibition of p70s6k and down-regulation of c-myc, cyclin D1, cyclin A, and proliferating cell nuclear antigen. 1099 86

A new non peptidomimetic farnesyltransferase inhibitor, RPR-115135, was studied in an isogenic cell model system consisting of human colon cancer HCT-116 line. HCT-116 cells were transfected with an empty control pCMV vector or with a dominant-negative mutated p53 transgene to disrupt p53 function. Growth inhibitory effects of RPR-115135 were evaluated on cells growing under different conditions (serum starvation, serum starvation and recovery, nocodazole treatment). The cytotoxic activity of RPR-115135 was independent of the cell cycle status of the target cells. Addition of RPR-115135 only to cells exposed to reduced serum conditions (0.1% FCS) resulted in an enhanced ability of HCT-116 cells to arrest in the G0/G1 phase. This arrest response appeared independent of p53/p21cip1/waf-1 function. A reduction of Cyclin A protein amount by RPR-115135 was observed in both clones. These latter results suggest that RPR-115135 might down-regulate the cell cycle factor that would normally impede G0/G1 arrest.
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PMID:RPR-115135, a new non peptidomimetic farnesyltransferase inhibitor, induces G0/G1 arrest only in serum starved cells. 1125 Nov 85

To investigate the relationship between oncogene activation and induction of micronuclei by a new non-peptidic mimetic farnesyltransferase inhibitor, RPR-115135, two isogenic cell lines, human colon cancer line HCT-116, which harbors a K-ras mutation, and spontaneously immortalized human breast epithelial cell line MCF-10A, were utilized. HCT-116 cells were transfected with an empty control pCMV vector (clone CMV-2) or with a dominant negative mutated p53 transgene (clone Mu-p53-2) to disrupt p53 function. In both clones RPR-115135 induced a significant increase in the frequency of micronucleation at concentrations that did not affect cell membrane integrity. RPR-115135 produced a significant increase in the ratio of CREST+ to CREST- micronuclei. MCF-10A cells were stably transfected with either c-Ha-ras or c-erbB-2 or both H-ras + c-erbB-2. No induction of micronuclei was observed. No induction of micronuclei was reported in human lymphocytes and in primary spinal cells obtained from 7-day chick embryos. In conclusion, RPR-115135 acts as an aneugenic agent in a complex manner, dependent upon the complement of mutations in cell regulatory genes in tumour cells and this activity may be independent of ras genotype.
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PMID:Induction of micronuclei by a new non-peptidic mimetic farnesyltransferase inhibitor RPR-115135: role of gene mutations. 1150 42

A new nonpeptidic farnesyltransferase inhibitor, RPR-115135, in combination with 5-fluorouracil (5-FU) was studied in an isogenic cell line model system consisting of human colon cancer HCT-116 cells. HCT-116 cells were transfected with an empty control pCMV vector and with a dominant-negative mutated p53 transgene (248R/W). We found that, relative to control transfectants, there was a slight tendency for the p53 inactivated cells to be less sensitive to 5-FU after 6 days of continuous treatment. Simultaneous administration of RPR-115135 and 5-FU, at equitoxic concentrations, resulted in an enhancement of 5-FU cytotoxicity, especially in the CMV-2 clone. Growth inhibition could be accounted for on the basis of a specific cell cycle arrest phenotype (G(2)-M arrest in CMV-2 and S arrest in mutated clones), as assayed by flow cytometry. The combination RPR-115135 + 5-FU increases apoptotic events only in the CMV-2 clone.
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PMID:Nonpeptidomimetic farnesyltransferase inhibitor RPR-115135 increases cytotoxicity of 5-fluorouracil: role of p53. 1175 20

A new non peptidic farnesyltransferase inhibitor, RPR-115135, in combination with 5-FU was studied in 10 human colon cancer cell lines (HCT-116, RKO, DLD-1, Colo-320, LoVo, SW-620, HT-29, HCT-15, Colo-205 and KM-12) carrying several mutations but well characterized for p53 and Ras status. We found that there was a slight tendency (not statistically significant) for the p53 inactivated cells to be less sensitive to 5-FU after 6 days continuous treatment. Simultaneous administration of RPR-115135 and 5-FU, at subtoxic concentrations, resulted in a synergistic enhancement of 5-FU cytotoxicity in the p53 wildtype cells (HCT-116, RKO, DLD-1, Colo-320, LoVo). In the p53 mutated cells (SW-620, HT-29, HCT-15, Colo-205, KM-12) the effect was very complicated. In HCT-15 the combination resulted in antagonism, in KM-12 in antagonism or in synergy (at different concentrations) and in SW-620, HT-29 and Colo-205 cells in synergy but only when 5-FU was administered at high concentrations. Growth inhibition could be accounted for on the basis of a specific cell cycle arrest phenotype (G2-M arrest), as assayed by flow cytometry, only in the p53 functioning cell lines. The combination RPR-115135 + 5-FU increases apoptotic events only in these cell lines. In the mutated cell lines no major alterations on cell cycle arrest phenotype and no induction of apoptosis was observed. Although RPR-115135 can potentiate the effect of 5-FU in cells in which p53 function is disrupted, these data suggest strongly that RPR-115135 significantly enhances the efficacy of 5-FU only when p53 is functioning.
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PMID:RPR-115135, a farnesyltransferase inhibitor, increases 5-FU- cytotoxicity in ten human colon cancer cell lines: role of p53. 1211 40

A number of small GTPases are involved in cancer cell proliferation, migration and invasion. They need to be prenylated for full biological functions. We have recently reported that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, which block the biosynthesis of farnesylpyrophosphate and geranylgeranylpyrophosphate, inhibit in vitro invasion of human pancreatic cancer cells. In the present study, we examined the effects of two selective inhibitors of prenylation, a farnesyltransferase inhibitor (FTI-277) and a geranylgeranyltransferase type I inhibitor (GGTI-298), on in vitro invasion of cancer cells in a modified Boyden chamber assay. The invasion of COLO 320DM human colon cancer cells was inhibited potently by HMG-CoA reductase inhibitor lovastatin and GGTI-298 but weakly by FTI-277. The treatment of cancer cells with GGTI-298 markedly caused RhoA to decrease in the membrane fraction and accumulate in the cytosolic fraction, whereas it had almost no effect on the translocation of Ras. FTI-277 markedly inhibited membrane localization of Ras, but its inhibitory effect on cancer cell invasion occurred only at doses that affected membrane localization of RhoA. FTI-277 and GGTI-298 decreased the growth potential of COLO 320DM cells, but the inhibitory effect of GGTI-298 was rather selective toward invasion in association with changes in cell morphology and RhoA localization. These results suggest that geranylgeranylation of RhoA by geranylgeranyltransferase type I is critical for cancer cell invasion, and inhibition of geranylgeranyltransferase type I activity should offer a novel approach to the treatment of invasion and metastasis of cancer cells resistant to farnesyltransferase inhibitors.
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PMID:Selective inhibition of cancer cell invasion by a geranylgeranyltransferase-I inhibitor. 1459 91

To examine the drug efficacy of a novel farnesyltransferase inhibitor (FTI), CH4512600, in vivo, we developed a reliable liver metastasis model of human colon cancer using NOD/Shi-scid IL2Rgamma(null) (NOG) mice. Eleven human colon cancer cell lines were examined for their ability to form diverse metastatic foci in the livers of NOG mice. When inoculated with 10(4) COLO320DM, HCT 116, HT-29, WiDr, LoVo and LS174T cells, liver metastasis was evident in 100% (6/6), 100% (6/6), 88.9% (8/9), 87.5% (7/8), 83.3% (5/6) and 50.0% (3/6) of the NOG mice, respectively. CaCo2, COLO201, LS123, SW48 and SW1417 showed no metastasis when seeded at 10(4) cells even in NOG mice. The mRNA expression levels and genetic mutations of N, H and K-RAS genes, which directly affect the levels of cellular RAS protein that would be molecular target for FTI, were also examined in these six metastatic human colon cancer cell lines for molecular biological and genotypic characteristics. Only three cell lines had a point mutation in the RAS oncogene. LS174T cell line had a point mutation of the K-RAS gene at codon 12 (gly12 --> asp; G12D), and HCT 116 and LoVo cell lines had a point mutation of the K-RAS gene at codon 13 (gly13 --> asp; G13D). Relative gene expression levels of N, H and K-RAS genes in the HCT 116 cell line were 2.6-5.0-fold lower than that of LS174T and LoVo cell lines. We selected HCT 116 cell line from our liver metastasis model for evaluation of FTI CH4512600 efficacy in vivo. Using the NOG mouse liver metastasis model, we demonstrated the effectiveness of FTI CH4512600 to suppress tumor growth in vivo and to prolong mouse survival significantly from 36.9+/-2.9 to 50.3+/-9.4 days.
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PMID:Liver metastasis models of colon cancer for evaluation of drug efficacy using NOD/Shi-scid IL2Rgammanull (NOG) mice. 1809 54

In this review, we summarize recent progress regarding the study of the main enzymes of lipid metabolism involved in colorectal cancer development, namely of a) farnesyltransferase (Ftase), a cytosolic enzyme that catalyzes the first step in the protein farnesylation; b) farnesyl diphosphate synthase (FPPS, which yields FPP, a substrate for Ftase; c) fatty acid synthase (FAS), an enzyme required for the conversion of acetyl-CoA and malonyl-CoA to palmitate; and d) lipoprotein lipase (LPL), the crucial enzyme for intravascular catabolism of triglyceride-rich lipoproteins. Alterations in the levels of these enzymes may contribute to a cell growth advantage acquired during the carcinogenic process and to the development of malignancy. We have demonstrated an elevated Ftase activity in human colorectal cancer (CRC), with differences in Ftase activity related to histological grading, tumor location and KRAS mutation status. Moreover, the first evidence of FPPS activity in human CRC was demonstrated by our study, where a higher FPPS activity and mRNA expression was present in cancer rather than in normal mucosa. We also detected a hyperactivation of FAS in colon cancer, related to tumor location, sex and, p53 mutation status. Our data reinforce the role of lipid metabolism in the regulation of cellular metabolic processes and in carcinogenesis. Moreover, our findings suggest that biological factors including sex, gene mutation status, as well as the stratification of patients with colorectal cancer into right- and left-sided subsets may be important in patient selection for targeted therapies. Our studies in vitro demonstrated that FAS might also be a molecular target for the antiproliferative activity of olive oil polyphenols in a metabolically defined subset of patients with colon cancer. Moreover, we detected that the serum levels of FAS in patients with colorectal cancer are associated with tumor stage. Recently, we found a significant reduction in the levels of FAS and another lipogenic enzyme, LPL, in adipose tissue adjacent to tumor lesions, compared to the levels of FAS detected in paired tissue distant from neoplasia in patients with colorectal cancer. The study of metabolic changes in lipogenic enzyme pathways, as well as the determination of the distribution of individual roles within each biochemical pathway provide a rationale for selecting a particular reaction step suitable for therapeutic intervention.
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PMID:A significant role of lipogenic enzymes in colorectal cancer. 2275 16

In the incessant search for innovative cancer control strategies, this study was devoted to the design, synthesis and pharmacological evaluation of dual inhibitors of farnesyltransferase and tubulin polymerization (FTI/MTIs). A series of indolizine-phenothiazine hybrids 16 (amides) and 17 (ketones) has been obtained in a 4-step procedure. The combination of the two heterocycles provided potent tubulin polymerization inhibitors with similar efficiency as the reference phenstatin and (-)-desoxypodophyllotoxin. Ketones 17 were also able to inhibit human farnesyltransferase (FTase) in vitro. Interestingly, three molecules 17c, 17d and 17f were very effective against both considered biological targets. Next, nine indolizine-phenothiazine hybrids 16c, 16f, 17a-f and 22b were evaluated for their cell growth inhibition potential on the NCI-60 cancer cell lines panel. Ketones 17a-f were the most active and displayed promising cellular activities. Not only they arrested the cell growth of almost all tested cancer cells, but they displayed cytotoxicity potential with GI₅₀ values in the low nanomolar range. The most sensitive cell lines upon treatment with indolizine-phenothiazine hybrids were NCI-H522 (lung cancer), COLO-205 and HT29 (colon cancer), SF-539 (human glioblastoma), OVCAR-3 (ovarian cancer), A498 (renal cancer) and especially MDA-MB-435 (melanoma). Demonstrating the preclinical effectiveness of these dual inhibitors can be crucial. A single dual molecule could induce a synergy of antitumor activity, while increasing the effectiveness and reducing the toxicity of the classical combo treatments currently used in chemotherapy.
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PMID:Indolizine-phenothiazine hybrids as the first dual inhibitors of tubulin polymerization and farnesyltransferase with synergistic antitumor activity. 3289 61


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