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)

We report the first mutational study of thymidine kinase 1 (TK1) performed in human solid tumors. We sequenced cDNAs representing the complete coding region of TK1 in human breast (n=22) and colorectal (n=26) cancer. Codon 106 near the ATP binding site constantly differed (ATG --> GTG; Met --> Val) from the one deposited by Bradshaw and Deininger in the Genbank database (Accession number NM_003258). Silent polymorphisms at codon 11 (CCC --> CCT; Pro --> Pro) and codon 75 (GCG --> GCA; Ala --> Ala) were frequently detected in tumors as well as in normal tissues. In breast cancer the two polymorphisms were observed in 63.6% of the samples analyzed. No significant association could be found between polymorphisms and TK activity. In colorectal cancer the incidence of the two changes was 73.1% and 69.2%, respectively. Interestingly, one colon cancer with high cytosolic TK activity displayed two missense mutations located in and near the putative phosphorylation site by tyrosine kinase (s) (TAT --> CAT; Tyr --> His) and by cAMP-, cGMP-dependent protein kinase (TAC --> TGC; Tyr --> Cys), respectively; adjacent normal mucosa showed no mutation. This may open new avenues that imply TK1 activity in tumor cell proliferation.
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PMID:Mutation analysis in the coding sequence of thymidine kinase 1 in breast and colorectal cancer. 1269 56

Proper antigen presentation is paramount to the induction of effective and persistent antitumor immune responses. In a murine model of hepatic metastasis of colon cancer, we found that the numbers of in situ mature dendritic cells (DCs) and macrophages in tumor-infiltrating leukocytes (TILs) were significantly increased in mice treated with the combination therapy of herpes simplex virus thymidine kinase, interleukin 2, and GM-CSF genes when compared with control groups without GM-CSF treatment. Significantly higher levels of IFN-gamma, MIP-1 alpha, mIL-12, and GM-CSF were detected in the tumor after the combination therapy. T cells isolated from the combination therapy-treated mice exhibited higher ex vivo direct CTL activity than those from other treatment groups. Antigen-presenting cells (APCs) enriched from the TILs and liver of the combination therapy-treated mice induced higher levels of proliferation by the splenocytes from long-term surviving mice that had been cured of tumors at early time points (days 4 and 7) whereas significant APC activity was only observed in the spleen at the latter time point (day 7, 14) after the combination therapy. In contrast, APCs isolated from tk or tk + IL-2-treated mice did not induce any significant proliferation. Subcutaneous injection of fluorescence-labeled latex microspheres followed by the combination therapy showed a similar sequential trafficking of microspheres, day 4 after the combination therapy to tumor and day 14 to spleen. The results suggest that APCs recruited by intratumoral gene delivery of GM-CSF can capture antigens, mature to a stage suitable for antigen presentation, and subsequently migrate to the spleen where they can efficiently stimulate antigen-specific T cells.
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PMID:In situ recruitment of antigen-presenting cells by intratumoral GM-CSF gene delivery. 1295 80

(E)-2'-Deoxy-2'-(fluoromethylene) cytidine (FMdC), an inhibitor of ribonucleotide diphosphate reductase (RR), is a potent radiation-sensitiser acting through alterations in the deoxyribonucleoside triphosphate (dNTP) pool in the de novo pathway to DNA synthesis. The activity of thymidine kinase (TK), a key enzyme in the 'salvage pathway', is known to increase in response to a lowering of dATP induced by FMdC. Nucleoside analogues such as iododeoxyuridine (IdUrd) are incorporated into DNA after phosphorylation by TK. Radiation sensitisation by IdUrd depends on IdUrd incorporation. Therefore, we have investigated the radiosensitising effect of the combination of FMdC and IdUrd on WiDr (a human colon cancer cell-line) and compared it to the effect of either drug alone. We analysed the effects of FMdC and IdUrd on the dNTP pools by high-performance liquid chromatography, and measured whether the incorporation of IdUrd was increased by FMdC using a [(125)I]-IdUrd incorporation assay. The combination in vitro yielded radiation-sensitiser enhancement ratios of >2, significantly higher than those observed with FMdC or IdUrd alone. Isobologram analysis of the combination indicated a supra-additive effect. This significant increase in radiation sensitivity with the combination of FMdC and IdUrd could not be explained by changes in the dNTP pattern since the addition of IdUrd to FMdC did not further reduce the dATP. However, the increase in the radiation sensitivity of WiDr cells might be due to increased incorporation of IdUrd after FMdC treatment. Indeed, a specific and significant incorporation of IdUrd into DNA could be observed with the [(125)I]-IdUrd incorporation assay in the presence of 1 microM unlabelled IdUrd when combined with FMdC treatment.
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PMID:Positive interactive radiosensitisation in vitro with the combination of two nucleoside analogues, (E)-2'-deoxy-2'-(fluoromethylene) cytidine and iododeoxyuridine. 1519 42

We evaluated the antitumor effects of combination gene therapy on CT26 mouse colon cancer cells, using the genes for herpes simplex virus thymidine kinase gene HSV-TK combined with granulocyte macrophage colony-stimulating factor (GM-CSF) compared with HSV-TK alone. Cells, unmodified or retrovirally transduced with HSV-TK or GM-CSF, were inoculated subcutaneously into syngeneic BALB/c mice in various combinations. HSV-TK and GM-CSF were also delivered using different routes (in separate cells vs doubly transfected single cells). Both HSV-TK (with i.p. ganciclovir - GCV - treatment) and GM-CSF genes had independent antitumor effects, and given together they caused significant reduction in tumor volumes compared with the HSV-TK gene alone (P < 0.001). Following GCV treatment, however, the treated/control ratios for tumor volumes were not different between tumors containing either HSV-TK alone or both genes (0.27 vs 0.25, respectively). Thus, the presence of GM-CSF did not increase the bystander effect of HSV-TK. Tumors receiving genes transferred in separate cells tended to be more consistently suppressed after GCV treatment than when both genes were transferred in the same cells, although this was not statistically significant. Thus, combination GM-CSF and HSV-TK gene therapy produced greater therapeutic efficacy than HSV-TK alone, but the bystander effect was not enhanced by GM-CSF.
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PMID:Herpes simplex virus thymidine kinase and granulocyte macrophage colony-stimulating factor combination gene therapy in a murine CT26 cell colon cancer model. 1523 2

Transduction of tumor cells with herpes simplex virus thymidine kinase (HSV-tk) gene and subsequent treatment with the prodrug ganciclovir (GCV) is the most common system utilized to date for "suicide" gene therapy of cancer. In the current report, we show that HSV-tk gene transduction enhances tumor growth rate of murine colon cancer cells, that are implanted subcutaneously in syngeneic mice, and enhances cyclooxygenase-2 (COX-2) protein expression and prostaglandin E(2) (PGE(2)) release in vitro and in vivo. It is further shown that the observed phenomenon is related to the presence of the HSV-tk sequence insert in the retroviral vector used for HSV-tk gene delivery. Transduction of murine colon cancer cells with control vector, carrying the neomycin-resistance gene alone, failed to increase tumor growth rate and COX-2 protein expression or PGE(2) production. On the contrary, it even decreased tumor growth, COX-2 protein expression and PGE(2.) The growth rate of HSV-tk-transduced murine tumors was significantly reduced by treatment with the selective COX-2 inhibitor nimesulide. Additionally, we demonstrate herein that both enhanced growth rate of HSV-tk-transduced murine tumors and increased levels of PGE(2) in HSV-tk-transduced cells persist upon the development of GCV resistance. Taken together, these results provide a better understanding of the direct effect of HSV-tk gene transduction on tumor cell biology and target tumor development.
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PMID:Herpes simplex virus thymidine kinase gene transduction enhances tumor growth rate and cyclooxygenase-2 expression in murine colon cancer cells. 1535 92

We investigated on colon cancer cells the effect of geraniol on thymidylate synthase and thymidine kinase expression, two enzymes related to 5-fluorouracil cytotoxicity. The anti-tumoral efficacy of geraniol and 5-fluorouracil were also evaluated on TC-118 human tumors transplanted in Swiss nu/nu mice. Geraniol (150 microM) but not 5-fluorouracil caused a 2-fold reduction of thymidylate synthase and thymidine kinase expression in cancer cells. In nude mice, the combined administration of 5-fluorouracil (20 mg/kg) and geraniol (150 mg/kg) caused a 53% reduction of the tumor volume, whereas a 26% reduction was obtained with geraniol alone, 5-fluorouracil alone showed no effect.
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PMID:Geraniol, a component of plant essential oils, modulates DNA synthesis and potentiates 5-fluorouracil efficacy on human colon tumor xenografts. 1537 32

In humans, no efficient treatment exists not only against multifocal liver metastases (LM) but also against recurrent microscopic liver metastases within the liver remnant following curative liver resection. Furthermore, in nonmultifocal LM, partial liver resection could be performed, but in more than 50% of the patients, tumor recurrence within liver remnant is observed, partly due to the growth of dormant cancer cells in the setting of postoperative host immune dysfunction. We investigated the therapeutic potential of interleukin-12 (IL-12) immuno-gene therapies in these experimental models under total vascular exclusion (TVE) of the liver. In rats with multiple LM of DHDK12 colon cancer cells, we observed a significant reduction in tumor volume after retroviral-mediated gene transfer of either herpes simplex virus thymidine kinase (HSV1-TK) and ganciclovir (GCV) administration, or IL-12. Combined treatment with HSV1-TK/GCV and IL-12 resulted in improved tumor volume reduction and even survival. In rats with recurrent microscopic DHDK12 LM established after partial liver resection, we observed significantly decreased recurrent tumor volumes and increased survival after retroviral-mediated IL-12 gene transfer. In both settings, immunohistological analysis revealed that IL-12 immuno-gene therapy was accompanied by an infiltration of CD8+ T lymphocytes within the tumors. Altogether, our results suggest that IL-12 adjuvant gene therapy could improve the management of patients with either resectable or unresectable LM.
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PMID:Adjuvant interleukin-12 gene therapy for the management of colorectal liver metastases. 1547 16

Conditionally replicating adenoviruses (CRAds) selectively replicate in and thereby kill cancer cells. The CRAd AdDelta24 with pRb-binding-deficient E1A kills cancer cells efficiently. Arming CRAds with genes encoding prodrug-converting enzymes could allow for enhanced anticancer efficacy by the combined effects of oncolytic replication and local prodrug activation. Here, we investigated combination treatment of human colon cancer cell lines with AdDelta24-type CRAds and gene-directed enzyme prodrug therapy (GDEPT) using two different enzyme/prodrug systems, that is, thymidine kinase/ganciclovir (TK/GCV) and carboxylesterase (CE)/CPT-11. On all three cell lines tested, GDEPT with TK/GCV made CRAd treatment less efficacious. In contrast, expression of a secreted form of CE (sCE2) combined with CPT-11 treatment markedly enhanced the efficacy of AdDelta24 virotherapy. Based on this observation, we constructed an AdDelta24 variant expressing sCE2. In the absence of CPT-11, this new CRAd Ad5-Delta24.E3-sCE2 was similarly effective as its parent in killing human colon cancer cells. Low concentrations of CPT-11 inhibited Ad5-Delta24.E3-sCE2 propagation. Nevertheless, CPT-11 specifically augmented the cytotoxicity of Ad5-Delta24.E3-sCE2 against all three-colon cancer cell lines. Hence, the positive contribution of sCE2/CPT-11 GDEPT to colon cancer cytotoxicity outweighed its negative influence on CRAd propagation. Therefore, CRAd-sCE2/CPT-11 combination therapy appears useful for more effective treatment of colon cancer.
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PMID:Gene-directed enzyme prodrug therapy with carboxylesterase enhances the anticancer efficacy of the conditionally replicating adenovirus AdDelta24. 1572 67

Cancer cells transcriptionally activate many genes that are important for uncontrolled proliferation and cell death. Deregulated transcriptional machinery in tumor cells usually consists of increased expression/activity of transcription factors. Ideally, cancer-specific killing can be achieved by delivering a therapeutic gene under the control of the DNA elements that can be activated by transcription factors that are overexpressed and/or constitutively activated in cancer cells. Additionally, tumor-specific translation of tumor-killing genes has been also exploited in cancer gene therapy. Based on these rationales, cancer-specific expression of a therapeutic gene has emerged as a potentially successful approach for cancer gene therapy. To achieve tumor-specific expression, cancer-specific vectors are generally composed of promoters, enhancers, and/or 5'-UTR that are responsive to tumor-specific transcription factors. A number of cancer-specific promoters have been reported, such as those of probasin, human telomerase reverse transcriptase, survivin, ceruloplasmin, HER-2, osteocalcin, and carcinoembryonic antigen. Evidences suggest that the enhancer element targeted by beta-catenin can be useful to target colon cancer cells. The 5'-UTR of the basic fibroblast growth factor-2 has been reported to provide tumor specificity. Moreover, a variety of therapeutic genes demonstrated direct antitumor effects such as those encoding proapoptotic proteins p53, E1A, p202, PEA3, BAX, Bik, and prodrug metabolizing enzymes, namely thymidine kinase and cytosine deaminase. As cancerous cells of different origins vary significantly in their genetic, transcriptional/translational, and cellular profiles, the success of a cancer gene therapy will not be promised unless it is carefully designed based on the biology of a specific tumor type. Thus, tremendous research efforts have been focused on the development of non-viral vectors that selectively target various tumors resulting in minimal toxicity in the normal tissues. Significant progresses were also made in the exploitation of various novel apoptotic, cytotoxic genes as therapeutic tools that suppress the growth of different tumors. Together, these recent advances provide rationales for future clinical testing of transcriptionally targeted non-viral vectors in cancer patients.
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PMID:Cancer-specific gene therapy. 1609 14

Suicide gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system is a well-characterized tool for cancer gene therapy; however, it does not yet exhibit sufficient efficacy to cure patients of malignancies. We have reported that adenovirally delivered monocyte chemoattractant protein (MCP)-1 augmented the antitumor effects of the HSV-tk/GCV system in an athymic nude mouse model. The current study, which uses an immunocompetent mouse model of colon cancer, was designed to evaluate the antitumor effects of MCP-1 gene delivery in conjunction with this suicide gene therapy system. Subcutaneous tumor foci were directly transduced with both recombinant adenoviruses (rAds) expressing an HSV-tk gene and either of the MCP-1, CD80 and LacZ genes, followed by GCV administration. The growth of tumors was markedly suppressed by codelivery of HSV-tk and MCP-1 genes, which was exclusively associated with the recruitment of monocytes/macrophages, T helper 1 (Th1) cytokine gene expression and cytotoxic activity of the splenocytes. Furthermore, the antitumor effects were more efficient than that obtained by the combination of HSV-tk and CD80 genes. These results suggest an immunomodulatory effect of MCP-1 in the context of suicide gene therapy of colon cancer via orchestration of innate and acquired immune responses.
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PMID:Monocyte chemoattractant protein-1 gene delivery enhances antitumor effects of herpes simplex virus thymidine kinase/ganciclovir system in a model of colon cancer. 1622 95


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