UMLS:C0699790 - FACTA Search

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

JC polyoma virus (JCV) is known to be the cause of the degenerative central nervous system white matter disease progressive multifocal leucoencephalopathy. Recently, JCV DNA has unexpectedly been found in significant quantity in normal colon mucosa and in tissue from colonic carcinomas, with increased quantities in the cancerous tissues. The yield of JCV DNA was increased by use of topoisomerase I, possibly because the JCV DNA was negatively supercoiled. The causes of ulcerative colitis (in which colon cancer is common) and multiple sclerosis are not known. Here I suggest that JCV may play a role in the pathogenesis of these diseases, and discuss methods for testing this hypothesis.
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PMID:Is JC polyoma virus the cause of ulcerative colitis and multiple sclerosis? 1100 63

BNP1350, 7-[(2-trimethylsilyl)ethyl]-20(S)-camptothecin, is a novel semi-synthetic, highly lipophilic, silicon-containing camptothecin and an inhibitor of topoisomerase I. It has been supercomputer engineered for superior oral bioavailability, superior lactone stability, broad anti-tumor activity, increased potency and insensitivity to Pgp/MRP/LRP drug resistance. We determined the efficacy of BNP1350 in experimental human colon cancer and compared its anti-tumor effects with those of CPT-11/SN-38. We also determined a possible influence of Pgp, MRP and LRP on the efficacy of BNP1350. The in vitro anti-proliferative capacity of the compounds using various exposure times was assessed in five colon cancer cell lines and indicated that BNP1350 was similarly effective or slightly more potent than SN-38. Four cell lines of other origin with sublines expressing Pgp, MRP and/or LRP showed that BNP1350 was significantly more effective than SN-38 (p < 0.05) and that the activity of BNP1350 was not reduced in multidrug-resistant cells. For in vivo experiments, BNP1350 was given 1.0 mg/kg i.p. or 1.5 mg/kg p.o. daily x 5 and CPT-11 20 mg/kg i.p. daily x 5 being equitoxic schedules in nude mice bearing s.c. human tumor xenografts. The schedules were studied in colon cancer xenografts COLO320, COLO205 or WiDr as well as in two Pgp-positive xenografts 2780AD and BRO/mdr1.1 and the parental Pgp-negative A2780 ovarian cancer xenografts and BRO melanoma xenografts. Growth inhibition of >50% was obtained for BNP1350 given i.p. in six out of the seven xenografts studied. BNP1350 was similarly effective when given i.p. or p.o. CPT-11 was as effective as BNP1350, except in BRO and BRO/mdr1.1 xenografts. Pgp expression in xenografts in vivo confirmed that there was no negative influence on the efficacy of BNP1350. In conclusion, BNP1350 shows a broad spectrum of activity in experimental human tumors and is a suitable candidate for oral treatment of cancer.
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PMID:New highly lipophilic camptothecin BNP1350 is an effective drug in experimental human cancer. 1100 78

New drug development requires simple in vitro models that resemble the in vivo situation more in order to select active drugs against solid tumours and to decrease the use of experimental animals. In this paper, we review the characteristics and scope of a relatively simple cell-culture system with a three-dimensional organisation pattern - the multilayered postconfluent cell culture model. Solid tumour cell lines from diverse origins when grown in V-bottomed microtiter plates reach confluence in 3-5 days and then start to form multilayers. The initial exponential growth of the culture is followed by a plateau phase when cells reach confluence. This produces changes in the morphology of the cells. For some cell lines, it is possible to observe cell differentiation. A substantial advantage of the system is the use of the sulforodamine B (SRB) assay to determine relative cell growth or viability, which allows semiautomation of the experiments. Several experiments were performed to assess the differences and similarities between cells cultured as monolayers and multilayers, and eventually, compared with the results for solid tumours and some other models such as spheroids. Cell-cycle analysis for multilayers showed a lower S-phase arrest, which is accompanied by a decrease in the expression of cell-cycle-related proteins and a decrease in cellular nucleotide pools. Gene and protein expression of topoisomerase I, topoisomerase II and thymidylate synthase expression were lower for multilayers, but no substantial changes were observed for the expression of DT-diaphorase. P53 expression increased. Multilayer cultures present distinctive properties for drug transport across the membrane, drug accumulation and retention. In fact, the transport of antifolates across the membrane, accumulation of topotecan and gemcitabine-triphosphate are reduced in multilayers when compared with monolayers, which may be related to a decrease in drug penetration to the inner regions of the multilayers. Alteration of these pharmacodynamic parameters is directly related to a decrease in drug activity. The most powerful application of multilayers is in the assessment of cytotoxicity. Solid tumour cell lines from different origins have been treated with several conventional and investigational anticancer drugs. The data show that multilayers are more resistant to the drugs than the corresponding monolayers, but there are substantial differences between the drugs depending on culture conditions, e.g. the difference was rather small for a drug such as cisplatin, miltefosine and EO9, a drug, which is activated under hypoxic conditions. Gemcitabine was active against ovarian cancer but not against colon cancer, resembling the in vivo situation. This observation was not evident with monolayer experiments. Another interesting application is the possibility to perform drug combination studies. The combination of gemcitabine and cisplatin proved to produce selective cell kill in H322 cells (non-small cell lung cancer cell line). Neither of the drugs was independently able to produce similar effects. In summary, multilayer cultures are relatively simple three-dimensional systems to study the effect of microenvironmental conditions on anticancer drug activity. The model might serve as a base for a more rigorous secondary in vitro screening.
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PMID:The multilayered postconfluent cell culture as a model for drug screening. 1103 3

Translation of thymidylate synthase (TS) mRNA is controlled by its own protein end-product TS in a negative autoregulatory manner. Disruption of this regulation results in increased synthesis of TS and may lead to the development of cellular drug resistance to TS-directed anticancer agents. As a strategy to inhibit TS expression, antisense 2'-O-methyl RNA oligoribonucleotides (ORNs) were designed to directly target the 5' upstream cis-acting regulatory element (nucleotides 80-109) of TS mRNA. A 30 nt ORN, HYB0432, inhibited TS expression in human colon cancer RKO cells in a dose-dependent manner but had no effect on the expression of beta-actin, alpha-tubulin or topoisomerase I. TS expression was unaffected by treatment with control sense or mismatched ORNs. HYB0504, an 18 nt ORN targeting the same core sequence, also repressed expression of TS protein. However, further reduction in oligo size resulted in loss of antisense activity. Following HYB0432 treatment, TS protein levels were reduced by 60% within 6 h and were maximally reduced by 24 h. Expression of p53 protein was inversely related to that of TS, suggesting that p53 expression may be directly linked to intracellular levels of TS. Northern blot analysis demonstrated that TS mRNA was unaffected by HYB0432 treatment. The half-life of TS protein was unchanged after antisense treatment suggesting that the mechanism of action of antisense ORNs is mediated through a process of translational arrest. These findings demonstrate that an antisense ORN targeted at a critical cis-acting element on TS mRNA can specifically inhibit expression of TS protein in RKO cells.
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PMID:Effect of 2'-O-methyl antisense ORNs on expression of thymidylate synthase in human colon cancer RKO cells. 1113 11

JC virus (JCV), along with other members of the polyomavirus family, encodes a class of highly conserved proteins, T antigens, that are capable of inducing aneuploidy in cultured cells. We have previously isolated T-antigen DNA variants of JCV from both colon cancer tissues and the corresponding nonneoplastic gastrointestinal tissues, raising new questions about the role of JCV in the development of chromosomal instability of the colon. Based on the sequence of the transcriptional control region (TCR), JCV can be classified as archetype or tandem repeat variants. Among the latter, Mad-1, the prototype virus first isolated from a patient with progressive multifocal leukoencephalopathy, is characterized by lacking the 23- and 66-bp sequences that are present in the archetype and by duplication of a 98-bp sequence. In this study, we evaluated differences in the TCR of JCV isolated from colon cancer tissues and nonneoplastic epithelium. To characterize JCV variants, we first treated eight pairs of DNA samples from colon cancers and noncancerous tissue with topoisomerase I and then amplified and cloned the JCV TCR. We obtained 285 recombinant clones from the JCV TCR, 157 from nonneoplastic samples, and 128 from colon cancer tissues. Of these clones, 262 spanned the length of the JCV Mad-1 TCR: 99.3% from nonneoplastic samples and 82.8% from colon cancer tissues. In sequencing 54 clones in both directions, we did not find archetype JCV either in the nonneoplastic tissue or in the cancer samples. From all colon cancer tissues, 18 clones had a deletion of one 98-bp tandem repeat. This deleted strain was not detected in any of the nonneoplastic tissues (14 versus 0% [chi(2) = 23.6; P < 0.001]). Our study demonstrates that the only JCV strain present in the human colon is Mad-1, and the variant with a single 98-bp sequence is found exclusively in the cancer tissues. This strain may be involved in the development of chromosomal instability.
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PMID:Mad-1 is the exclusive JC virus strain present in the human colon, and its transcriptional control region has a deleted 98-base-pair sequence in colon cancer tissues. 1251 60

Identification of the molecular determinants of 5-fluorouracil (5-FU) and irinotecan (CPT-11) efficacy and toxicity is critically important for the development of more efficient and less toxic treatment strategies for patients with colon cancer. We have identified molecular predictors of response to chemotherapy with 5-FU and survival in patients with advanced colorectal cancer. Low gene expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) are associated with response and survival. Preliminary data suggest that gene expression levels of topoisomerase I, p21, bcl-2, and ICE may be predictive of response to therapy with CPT-11. Increased toxicity seen in patients treated with CPT-11 may be explained by polymorphism in the UGT1A1 gene, which is responsible for glucuronidation of the active metabolite of CPT-11.
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PMID:Determinants of prognosis and response to therapy in colorectal cancer. 1117 41

An intact lactone ring of camptothecins is a structural requirement for their anticancer activity. Propionate esters of camptothecin (CPT) and 9-nitrocamptothecin (9NC), CZ48 and CZ112, respectively, have been synthesized as derivatives resistant to lactone hydrolysis and are chemotherapeutically active. In this study, we have examined the mechanism of action of CZ48 and CZ112 and their distribution, metabolism, and toxicity. CZ112 incubated in human plasma retained its lactone structure longer than 9NC (t1/2: 10.5 and < 1 hr for CZ112 and 9NC, respectively). This resistance to lactone hydrolysis was also observed in mouse plasma or albumin solutions. Neither CZ48 nor CZ112 inhibit topoisomerase I and thus are prodrugs dependent on hydrolysis to CPT or 9NC, respectively. Rates of hydrolysis of CZ48 to CPT are higher by homogenates of mouse liver, spleen, lung, and kidney than by plasma. Rates of hydrolysis by tumor cells in culture vary and were higher by breast cancer and melanoma cells than by colon cancer cells. On the basis of these and other data, it is proposed that CZ48 and CZ112 may act as anticancer agents by resisting hydrolysis to camptothecins while in circulation. Hydrolysis in tissues may release intact lactone in target tissues.
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PMID:Pharmacology of camptothecin esters. 1119 97

Co-administration of synthetic chemically modified oligonucleotides with irinotecan, a selective topoisomerase I inhibitor, provided a significant enhancement in the antitumor activity of irinotecan. The enhancement of antitumor activity of irinotecan with co-administration of chemically modified oligonucleotides was observed in several tumor models--pancreatic cancer (Panc-1), colon cancer (HCT-116) and melanoma (A375). Inhibition of tumor growth in all three models required the co-administration of irinotecan and chemically modified oligonucleotides, but was independent of the nucleotide sequence of the oligonucleotides. The potentiation of antitumor activity was dependent on the dose of irinotecan and chemically modified oligonucleotides administered. The enhancement of antitumor activity of irinotecan was also observed by co-administration of a phosphorothioate oligonucleotide, however, to a lesser extent than did chemically modified oligonucleotides, suggesting that metabolic stability of the oligonucleotide contributes to the enhancement of antitumor activity seen with irinotecan. The co-administration of dextran sulfate sodium with irinotecan showed insignificant potentiation of antitumor activity of irinotecan, suggesting that the enhancement of antitumor activity of irinotecan observed was not a result of polyanionic characteristic of oligonucleotides. Co-administration of irinotecan and chemically modified oligonucleotides did not result in increased toxicity in the tumor models studied. Potentiation of antitumor activity of irinotecan observed with co-administration of oligonucleotides suggests that the oligonucleotides affect the pharmacokinetics and/or metabolism of irinotecan. The use of chemically modified oligonucleotides together with irinotecan may increase the therapeutic index of irinotecan in cancer patients and continued development of such agents should be considered.
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PMID:Potentiation of antitumor activity of irinotecan by chemically modified oligonucleotides. 1129 57

We studied the effects of Ukrain, a novel antitumor drug, on the activities of calcium, magnesium-dependent endonuclease (CME) and manganese-dependent endonuclease (MnDE) in rat liver nuclei, the activity of topoisomerase I assessed by pUC19 plasmid relaxation and CME activity in the nuclei of lymphocytes from colon cancer patients. Ukrain was found to exert a dose-dependent inhibiting effect on both CME and MnDE, similar to that exerted by erythropoietin, which was used as a reference preparation. Both Ukrain and erythropoietin also caused dose-dependent inhibition of topoisomerase I activity. The influence of Ukrain on CME activity in the nuclei of the lymphocytes of colon cancer patients was differential, depending on treatment efficacy. The results suggest that DNA-nicking enzymes may be a target of Ukrain and may mediate its antitumor effects.
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PMID:Effects of Ukrain on the activities of DNA-nicking enzymes. 1134 37

Colorectal cancer is one of the most frequent malignancies in humans and an important cause of cancer death. Metastatic colorectal cancer remains incurable with available systemic therapeutic options. The most active cytotoxic drug against this malignancy, the antimetabolite 5-fluorouracil, was developed more than forty years ago, and as a single agent produces responses in only 10 to 15% of patients which in general last less than one year. Efforts to ameliorate these poor results resulted in the 5-fluorouracil/leucovorin combination, which enhances response rates about two-fold, without, however, significantly improving survival rates. The recent emergence of a handful of new 5-fluorouracil analogues and folate antagonists, as well as the topoisomerase I inhibitor irinotecan, and the third-generation platinum compound oxaliplatin, is likely to alter this gloomy scenario. These agents are at least as effective as 5-fluorouracil in patients with advanced colorectal carcinoma, both untreated and previously treated with 5-fluorouracil-based regimens. This has led to the approval of irinotecan as second-line treatment for 5-fluorouracil-refractory disease, while the use of oxaliplatin has been suggested for patients having a defective 5-fluorouracil catabolism. Recently, FDA approved the combination of irinotecan with 5-fluorouracil and leucovorin for first-line treatment of advanced colon cancer. Based on the synergistic preclinical antitumor effects of some of these agents, their meaningful single-agent activity, distinct mechanisms of cytotoxicity and resistance, and only partially overlapping toxicity profiles, effective combination regimens are now being developed, which are likely to lead to a new, more hopeful era for patients suffering from advanced colorectal carcinoma.
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PMID:Irinotecan and oxaliplatin: an overview of the novel chemotherapeutic options for the treatment of advanced colorectal cancer. 1151 32

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