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 anticancer prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino-]carbonyloxycamptothecin (CPT-11) is a highly effective camptothecin analog that has been approved for the treatment of colon cancer. It is hydrolyzed by carboxylesterases to yield 7-ethyl-10-hydroxycamptothecin (SN-38), a potent topoisomerase I poison. However, upon high-dose intravenous administration of CPT-11, a cholinergic syndrome is observed that can be ameliorated by atropine. Previous studies have indicated that CPT-11 can inhibit acetylcholinesterase (AChE), and here, we provide a detailed analysis of the inhibition of AChE by CPT-11 and by structural analogs. These studies demonstrate that the terminal dipiperidino moiety in CPT-11 plays a major role in enzyme inhibition, and this has been confirmed by X-ray crystallographic studies of a complex of the drug with Torpedo californica AChE. Our results indicate that CPT-11 binds within the active site gorge of the protein in a fashion similar to that observed with the Alzheimer drug donepezil. The 3D structure of the CPT-11/AChE complex also permits modeling of CPT-11 complexed with mammalian butyrylcholinesterase and carboxylesterase, both of which are known to hydrolyze the drug to the active metabolite. Overall, the results presented here clarify the mechanism of AChE inhibition by CPT-11 and detail the interaction of the drug with the protein. These studies may allow the design of both novel camptothecin analogs that would not inhibit AChE and new AChE inhibitors derived from the camptothecin scaffold.
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PMID:The crystal structure of the complex of the anticancer prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11) with Torpedo californica acetylcholinesterase provides a molecular explanation for its cholinergic action. 1577 91

Rebeccamycin analogues containing uncommon sugars and substitutions on the imide nitrogen have been synthesized. Their cytotoxicities were tested in colon cancer and leukemia cells. Their ability to target topoisomerase I was examined using the in vivo complex of the topoisomerase bioassay in Hela cells. Compared with aglycon 1, the modified compounds with various sugar moieties showed more potent cytotoxicities and topo I targeting ability. In addition, the rebeccamycin analogues with various uncommon sugars showed distinct cytotoxicities and topo I targeting activities. The activity of compounds with 2-deoxyglucose (8 and 9) > compounds with 2,6-deoxyglucose (5 and 6) > compounds with 2,3,6-deoxyglucose (10). Furthermore, the anticancer activity of compounds correlated with their ability to target endogenous topo I. These results suggest that the sugar moiety, especially the 2-OH and 6-OH group of the sugar, rather than the modifications in imide structure on the indolocarbazole ring, is a key element for its activity.
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PMID:Syntheses and biological activities of rebeccamycin analogues with uncommon sugars. 1580 50

Recent evidence suggests that human O(6)-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein that protects the genome against mutagens and accords tumor resistance to many anticancer alkylating agents, may have other roles besides repair. Therefore, we isolated MGMT-interacting proteins from extracts of HT29 human colon cancer cells using affinity chromatography on MGMT-Sepharose. Specific proteins bound to this column were identified by electrospray ionization tandem mass spectrometry and/or Western blotting. These procedures identified >60 MGMT-interacting proteins with diverse functions including those involved in DNA replication and repair (MCM2, PCNA, ORC1, DNA polymerase delta, MSH-2, and DNA-dependent protein kinase), cell cycle progression (CDK1, cyclin B, CDK2, CDC7, CDC10, 14-3-3 protein, and p21(waf1/cip1)), RNA processing and translation (poly(A)-binding protein, nucleolin, heterogeneous nuclear ribonucleoproteins, A2/B1, and elongation factor-1alpha), several histones (H4, H3.4, and H2A.1), and topoisomerase I. The heat shock proteins, HSP-90alpha and beta, also bound strongly with MGMT. The DNA repair activity of MGMT was greatly enhanced in the presence of interacting proteins or histones. These data, for the first time, suggest that human MGMT is likely to have additional functions, possibly, in sensing and integrating the DNA damage/repair-related signals with replication, cell cycle progression, and genomic stability.
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PMID:Proteomic analysis of human O6-methylguanine-DNA methyltransferase by affinity chromatography and tandem mass spectrometry. 1622 12

CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) is an anticancer prodrug that has been approved for the treatment of colon cancer. It is a member of the camptothecin class of drugs and activation to the active metabolite SN-38, is mediated by carboxylesterases (CE). SN-38 is a potent topoisomerase I poison and is highly effective at killing human tumor cells, with IC50 values in the low nM range. However, upon high dose administration of CPT-11 to cancer patients, a cholinergic syndrome is observed, that can be rapidly ameliorated by atropine. This suggests a direct interaction of the drug or its metabolites with acetylcholinesterase (AChE). Kinetic studies indicated that CPT-11 was primarily responsible for AChE inhibition with the 4-piperidinopiperidine moiety, the major determinant in the loss of enzyme activity. Structural analogs of 4-piperidinopiperidine however, did not inhibit AChE, including a benzyl piperazine derivate of CPT-11. These results suggest that novel anticancer drugs could be synthesized that do not inhibit AChE, or alternatively, that novel AChE inhibitors could be designed based around the camptothecin scaffold.
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PMID:Inhibition of acetylcholinesterase by the anticancer prodrug CPT-11. 1625 98

Irinotecan hydrochloride, a camptothecin derivative, is one of the most effective drugs for colorectal cancer, and SN-38 is its main active metabolite. Development of resistance is a major obstacle to the clinical application of this drug. We established an SN-38-resistant subline from DLD-1 human colon cancer cells by continuous exposure to SN-38 and studied the mechanisms of resistance. The resistant subline (designated as DLDSNR6) had 10- to 100-fold higher resistance to camptothecin derivatives but showed no cross-resistance to doxorubicin, mitomycin C, and etoposide. DLDSNR6 cells carried a missense mutation in one allele of the DNA topoisomerase I gene that substituted glycine for serine at amino acid residue 365 accompanied by loss of the latter part of the remaining wild-type allele. Topoisomerase I expression was equal in DLDSNR6 and DLD-1 cells, but the nuclear extract of DLDSNR6 cells showed lower topoisomerase I catalytic activity. Moreover, exposure to camptothecin caused less accumulation of topoisomerase I-DNA complexes in DLDSNR6 cells than in DLD-1 cells. These findings suggest that the mutation interfered with both the catalytic activity of topoisomerase I and the stability of the ternary complex between topoisomerase I, DNA, and SN-38. This SN-38-resistant DLDSNR6 cell line may be useful for understanding the mechanisms of topoisomerase I function and drug-enzyme interactions.
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PMID:Novel missense mutation of the DNA topoisomerase I gene in SN-38-resistant DLD-1 cells. 1654 64

10-Hydroxycamptothecin (10-HCPT), an indole alkaloid isolated from a Chinese tree, Camptotheca acuminate, inhibits the activity of topoisomerase I and has a broad spectrum of anticancer activity in vitro and in vivo. However, its use has been limited due to its water-insolubility and toxicity with i.v. administration. The purpose of this study was to investigate the efficacy, toxicity and proper dosage of 10-HCPT as a single agent by oral administration in the treatment of human colon cancer. 10-HCPT significantly repressed the proliferation of Colo 205 cells at a relatively low concentration (5-20 nM). Flow cytometry analysis and western blot and apoptosis assays demonstrated that low-dose 10-HCPT arrested Colo 205 cells in the G2 phase of the cell cycle and triggered apoptosis through a caspase-3-dependent pathway. Moreover, following oral administration at doses of 2.5-7.5 mg/kg/2 days, significant suppression of tumor growth by 10-HCPT was observed in mouse xenografts. No acute toxicity was observed after an oral challenge of 10-HCPT in BALB/c-nude mice every 2 days. The results of this study suggest that a relatively low dose of 10-HCPT (p.o.) is able to inhibit the growth of colon cancer, facilitating the development of a new protocol of human trials with this anticancer drug.
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PMID:Anticancer effects of low-dose 10-hydroxycamptothecin in human colon cancer. 1659 97

The novel indolocarbazole edotecarin (J-107088, formerly ED-749) differs from other topoisomerase I inhibitors both pharmacokinetically and pharmacodynamically. In vitro, it is more potent than camptothecins and has a variable cytotoxic activity in 31 different human cancer cell lines. Edotecarin also possesses greater than additive inhibitory effects on cell proliferation when used in combination with other agents tested in vitro against various cancer cell lines. The present in vivo studies were done to extend the in vitro findings to characterize the antitumor effects of edotecarin when used either alone or in combination with other agents (i.e., 5-fluorouracil, irinotecan, cisplatin, oxaliplatin, and SU11248) in the HCT-116 human colon cancer xenograft model. Treatment effects were based on the delay in onset of an exponential growth of tumors in drug-treated versus vehicle control-treated groups. In all studies, edotecarin was active both as a single agent and in combination with other agents. Combination therapy resulted in greater than additive effects, the extent of which depended on the specific dosage regimen. Toxicity in these experiments was minimal. Of all 359 treated mice, the six that died of toxicity were in the high-dose edotecarin/oxaliplatin group. The results suggest that edotecarin may serve as effective chemotherapy of colon cancer when used as a single agent, in combination with standard regimens and other topoisomerase inhibitors or with novel agents, such as the multitargeted tyrosine kinase inhibitor SU11248.
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PMID:Antitumor efficacy of edotecarin as a single agent and in combination with chemotherapy agents in a xenograft model. 1667 81

Poly(ADP-ribose) polymerase (PARP) inhibitors enhance the antitumor activity of the topoisomerase I inhibitor irinotecan (CPT-11), which is used to treat advanced colorectal carcinoma. Since PARP inhibitors sensitize tumor cells also to the methylating agent temozolomide (TMZ) and clinical trials are evaluating CPT-11 in combination with TMZ, we tested whether the PARP inhibitor GPI 15427 (10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-one) increases the efficacy of CPT-11 + TMZ against colon cancer. Moreover, due to the ability of PARP inhibitors to avoid cell death consequent to PARP-1 overactivation, we evaluated whether oral administration of GPI 15427 provides protection from the dose-limiting intestinal toxicity of CPT-11. The results of colony formation assay indicated that GPI 15427 increased the antiproliferative effects (combination index <1) of TMZ + SN-38 (the active metabolite of CPT-11) against colon cancer cells. Accordingly, GPI 15427 (40 mg/kg/dayx5 days per os) in combination with TMZ (10 mg/kg/dayx5 days) + CPT-11 (4 mg/kg/dayx5 days) significantly reduced the growth of tumor xenografts. Oral administration of GPI 15427 (40 mg/kg/q2x3 days) prevented intestinal injury and diarrhea induced by CPT-11 (30 mg/kg/day x 3 days) reducing inflammation and PARP-1 overactivation, as evidenced by immunohistochemical staining of intestinal tissue with antipoly(ADP-ribose) antibody (Ab). In conclusion, the PARP inhibitor represents a novel strategy to enhance the antitumor efficacy and reduce toxicity of chemotherapy in colon cancer.
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PMID:Inhibition of poly(ADP-ribose) polymerase prevents irinotecan-induced intestinal damage and enhances irinotecan/temozolomide efficacy against colon carcinoma. 1680 34

RecQ helicase BLM-deficient cells are characteristically hypersensitive to 4-nitroquinoline-1-oxide (4NQO). We recently reported that isogenic BLM-deficient cells (PNSG13) are more sensitive than BLM-complemented cells (PNSF5) to camptothecin, which specifically traps topoisomerase I cleavage complexes (Top1cc). We now report that PNSG13 are also 3.5-fold more sensitive to 4NQO compared with PNSF5 and that 4NQO induces higher levels of Top1cc and reduced histone gamma-H2AX in PSNG13 than in PNSF5. Similarly, 4NQO induces more Top1cc in primary fibroblasts from a patient with Bloom syndrome than in normal human fibroblasts. 4NQO also induces Top1cc in colon cancer HCT116 and HT29 cells in a time- and concentration-dependent fashion. Of note, distinct from camptothecin, the Top1cc produced by 4NQO accumulate progressively after 4NQO addition and persist following 4NQO removal. The Top1cc induced by 4NQO are detectable by alkaline elution. To examine the functional relevance of the Top1cc induced by 4NQO, we used two stable topoisomerase I small interfering RNA (siRNA) cell lines derived from HCT116 and MCF7 cells. Both topoisomerase I siRNA cell lines are resistant to 4NQO, indicating that Top1cc contribute to the cellular activity of 4NQO. Collectively, these data show that 4NQO is an effective inducer of cellular Top1cc. Because 4NQO does not directly trap Top1cc in biochemical assays, we propose that active metabolites of 4NQO trap Top1cc by forming DNA adducts. Induction of Top1cc and histone gamma-H2AX by 4NQO may contribute to the cellular effects of 4NQO, including its selective activity toward RecQ helicase BLM-deficient cells.
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PMID:4-nitroquinoline-1-oxide induces the formation of cellular topoisomerase I-DNA cleavage complexes. 1681 25

The substituted chloroisoquinolinediones and pyrido[3,4-b]phenazinediones were synthesized, and the cytotoxic activity and topoisomerase II inhibitory activity of the prepared compounds were evaluated. Chloroisoquinolinediones have been prepared by the reported method employing 6,7-dichloroisoquinoline-5,8-dione. The cyclization to pyrido[3,4-b]phenazinediones was achieved by adding the aqueous sodium azide solution to the dimethylformamide solution of corresponding chloroisoquinoline-5,8-dione. The cytotoxicity of the synthesized compounds was evaluated by a SRB (Sulforhodamine B) assay against various cancer cell lines such as A549 (human lung cancer cell line), SNU-638 (human stomach cancer cell), Col2 (human colon cancer cell line), HT1080 (human fibrosarcoma cell line), and HL-60 (human leukemia cell line). Almost all the synthesized pyrido[3,4-b]phenazinediones showed greater cytotoxic potential than ellipticine (IC(50)=1.82-5.97 microM). In general, the cytotoxicity of the pyrido[3,4-b]phenazinediones was higher than that of the corresponding chloroisoquinolinediones. The caco-2 cell permeability of selected compounds was 0.62 x 10(-6)-35.3 x 10(-6)cm/s. The difference in cytotoxic activity among tested compounds was correlated with the difference in permeability to some degree. To further investigate the cytotoxic mechanism, the topoisomerase II inhibitory activity of the synthesized compounds was estimated by a plasmid cleavage assay. Most of compounds showed the topoisomerase II inhibitory activity (28-100%) at 200 microM. IC(50) values for the most active compound 6a were 0.082 microM. However, the compounds were inactive for DNA relaxation by topoisomerase I at 200 microM.
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PMID:Synthesis of 6-chloroisoquinoline-5,8-diones and pyrido[3,4-b]phenazine-5,12-diones and evaluation of their cytotoxicity and DNA topoisomerase II inhibitory activity. 1703 25


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