Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one (ARC-111) has potent TOP1-targeting activity and pronounced antitumor activity. Several analogues of ARC-111 were synthesized with NH2, N-alkyl, N,N-dialkyl, pyrrolidinyl, piperidinyl, and piperazinyl substituents at the 2-position of the 5-ethyl group. The relative TOP1-targeting activity and cytotoxicity of these structural analogues were assessed in RPMI8402 and P388 tumor cells and their camptothecin-resistant variants CPT-K5 and P388/CPT45, respectively. Potent TOP1-targeting activity was retained within a series of mono N-alkyl analogues that included NHCH2CH3, NHCH(CH3)2, and NHC(CH3)3. TOP1-targeting activity was diminished by the presence of a N-benzyl moiety. In a comparison of a series of N-alkyl-N-isopropyl analogues, activity decreased in the order CH3 > CH2CH3 > CH(CH3)2. Cytotoxicity in RPMI8402 and P388 did correlate with TOP1-targeting activity. Cytotoxic activity was also determined in KB3-1 cells and its variants KB/V-1 and KBH5.0. As KB/V-1 cells overexpress MDR1 and KBH5.0 cells overexpress BCRP, decreased cytotoxicity in these cell lines relative to the parent cell line is indicative of compounds that are substrates for these efflux transporters. In view of their diminished cytotoxicity in KB/V-1 cells, it appears that the likely demethylated metabolites of ARC-111, i.e., where NH2 or NHCH3 replaces the N(CH3)2 at the 2-position of the 5-ethyl substituent, are substrates for MDR1. In contrast, no significant difference in cytotoxicity among these three cell lines was observed with other N-alkyl analogues, including NHC2H5, NHCH(CH3)2, NHC(CH3)3, N(CH3)2, N(CH2CH3)2, NCH3(CH(CH3)2), and either the pyrrolidinyl or the piperidinyl analogues. The 2-(piperazinyl) analogues were associated with diminished cytotoxicity in KB/V-1 cells, suggesting that the second basic amino substituent is associated with their recognition as substrates by MDR1. Comparative studies on the antitumor activity of ARC-111 and its N-demethylated derivatives (the NHCH3 and NH2 analogues) against SJ-BT45 medulloblastoma xenografts in scid mice revealed that the secondary amine metabolite is at least as active as ARC-111 in vivo, although the primary amine derivative was significantly less potent.
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PMID:5-(2-aminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones: variation of n-alkyl substituents modulates sensitivity to efflux transporters associated with multidrug resistance. 1568 63

Human breast tumors often exist in an acidic and hypoxic microenvironment, which can promote resistance to radiation and chemotherapies. A tumor-selective pH gradient arises in these tumors which favors uptake and retention of drugs like camptothecin that are weak acids. We evaluated the effect of alkyl substitutions at the 7 position in seven CPTs with varying groups at the 10 position on modulation by acidic extracellular pH in three human breast cancer cell lines. Growth inhibition was assessed by propidium iodide staining of nucleic acids in human breast cancer cells cultured at either extracellular pH 6.8 or 7.4 that were (1) hormone-sensitive (MCF-7/wt), (2) hormone insensitive (MDA-MB-231), or (3) alkylator-resistant (MCF-7/4-hc). Over 10-fold pH modulation was observed in 7-halomethyl analogs of methylenedioxy-CPT and in 7-alkyl analogs of 10-amino-CPT. Of 39 analogs tested, the overall pattern of activity across breast tumor cell lines was similar with some notable exceptions. For example, 7-propyl-10-amino-CPT was modulated 16- to 20-fold by acidic extracellular pH in the MCF-7 cell lines, but only 6-fold in MDA-MB-231 cells. One mechanism that can contribute to pH modulation is enhanced cellular drug uptake and retention. In MCF-7/wt cells, uptake of 10-amino-CPT increased 4-fold, while retention increased over 10-fold at acidic extracellular pH. In addition, gene expression analysis of MCF-7/wt cells indicated that expression of a number of genes changed under acidic culture conditions, including down-regulation of the CPT efflux protein pump breast cancer resistance protein (BCRP). Interestingly, expression of topoisomerase I, the molecular target of CPT, was not affected by acidic growth conditions. These results highlight the importance of maintaining key features of tumor physiology in cell culture models used to study cancer biology and to discover and develop new anticancer drugs. While several substitutions at the 7 and 10 positions enhance potency, 7-halomethyl and 10-amino CPT analogs show selective activity at the acidic pH common to the microenvironment of most solid tumors.
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PMID:Camptothecin analogs with enhanced activity against human breast cancer cells. II. Impact of the tumor pH gradient. 1600 Nov 67

The details of molecular switching points between apoptosis and autophagy in tumor cells have still not been fully elucidated. This study focused on the role of cathepsin B and its substrate, BID as molecular links between apoptosis and autophagy in human breast cancer MCF-7 cells exposed to camptothecin. Apoptosis occurred rapidly with a peak in 60 min after drug administration, whereas autophagy developed at a much slower rate with continuous progression during 24 h of cell exposure to the drug. CPT induced very rapid activation of cathepsin B. Inhibition of cathepsins by E64d prevented CPT-induced BAX and BID aggregation on mitochondria and reduced significantly reduced apoptotic cell number. The above effects were accompanied by an increase in autophagosome formation, measured by expression of MAP I LC3. BID knock down resulted in strong suppression of CPT-induced apoptosis and a shift of cell death towards autophagy, manifesting with an increase of Beclin 1 and MAP I LC3 cellular content.
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PMID:Cathepsins and BID are involved in the molecular switch between apoptosis and autophagy in breast cancer MCF-7 cells exposed to camptothecin. 1607 1

To improve its aqueous solubility and stability in biological fluid, CPT was physically loaded in polymeric micelles. Polymeric micelles were composed of various poly(ethylene glycol)-poly(aspartate ester) block copolymers (PEG-P(Asp(R))). The incorporation and circulation stability of CPT micelles were evaluated by measuring the CPT in micelle using gel-permeation chromatography and by CPT concentration measurement after intravenous injection using HPLC, respectively, in terms of chemical structure of block copolymers. The stability of CPT-loaded micelles in vivo depended on the amount of benzyl esters, and length of PEG in the polymers to a greater degree than it did in vitro. A stable formulation of CPT-loaded micelles was obtained using PEG-P(Asp) with PEG of 5,000 (MW), 27 Asp units, and 57-75% benzyl esterification of Asp residue. This CPT-loaded micelles showed about a 17-fold lower blood clearance value than unstable micelles. The CPT-loaded micelles are potentially delivered to tumor sites owing to an extended circulation in the blood stream.
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PMID:Preparation of camptothecin-loaded polymeric micelles and evaluation of their incorporation and circulation stability. 1632 7

Tumors of the choroid plexus (CPT) are rare. While choroid plexus papillomas (CPP) are regarded as benign, choroid plexus carcinomas (CPC) have a dismal prognosis, and there is limited information available regarding the best treatment. Maximal possible surgery is generally believed to be the major prognostic factor, but data to answer the question, of whether second surgery improves the prognosis of CPC have been missing. A database of all cases of CPT reported in the literature until 2004 was created to determine prognostic factors and analyze therapeutic modalities. Eight hundred and fifty-seven cases of CPT were identified. Three hundred and forty-seven patients had CPC, 15 atypical choroid plexus papillomas (APP) and 495 CPP. Besides histology, complete resection was confirmed to be the most important prognostic factor in each of the subgroups defined by the three histological diagnoses. In CPP, complete resection was more frequently achieved (80.4%) than in APP (61.5%) or CPC (39.6%). Among the subgroup of incompletely resected CPC, 22.6% of the patients had second surgery. The prognosis of these patients appeared better when compared to incompletely resected CPC without second surgery (2-year overall survival 69% versus 30%). There was no such difference within the subgroup of CPP. This study suggests, if complete resection is not possible in the first surgery of a choroid plexus carcinoma, a second resection should be considered.
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PMID:Second surgery and the prognosis of choroid plexus carcinoma--results of a meta-analysis of individual cases. 1633 21

Fatty acid synthase (FAS) has been found to be overexpressed in a wide range of epithelial tumors, including breast cancer. Pharmacologic inhibitors of FAS cause apoptosis of breast cancer cells and result in decreased tumor size in vivo. However, how the inhibition of FAS induces apoptosis in tumor cells remains largely unknown. To understand the apoptotic pathway resulting from direct inhibition of FAS, we treated breast tumor cells with or without FAS small interfering RNA (siRNA) followed by a microarray analysis. Our results indicated that the proapoptotic genes BNIP3, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and death-associated protein kinase 2 (DAPK2) were significantly up-regulated on direct inhibition of the FAS gene. We also found that the knockdown of FAS expression significantly increased ceramide level in the tumor cells, and this increase was abrogated by acetyl-CoA carboxylase inhibitor. In addition, carnitine palmitoyltransferase-1 (CPT-1) inhibitor up-regulated the ceramide and BNIP3 levels in these cells, whereas treatment of tumor cells with FAS siRNA in the presence of a ceramide synthase inhibitor abrogated the up-regulation of BNIP3 and inhibited apoptosis. Furthermore, we found that treatment of cells with BNIP3 siRNA significantly counteracted the effect of FAS siRNA-mediated apoptosis. Consistent with these results, a significant inverse correlation was observed in the expression of FAS and BNIP3 in clinical samples of human breast cancer. Collectively, our results indicate that inhibition of FAS in breast cancer cells causes accumulation of malonyl-CoA, which leads to inhibition of CPT-1 and up-regulation of ceramide and induction of the proapoptotic genes BNIP3, TRAIL, and DAPK2, resulting in apoptosis.
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PMID:Mechanism of apoptosis induced by the inhibition of fatty acid synthase in breast cancer cells. 1674 Jul 34

Tumors of the choroid plexus (CPTs) are rare neoplasms of neuroectodermal origin usually arising in pediatric patients. However, CPT may occur at any age, and their distinction from metastatic carcinomas is often difficult in adult cases. Because CPTs frequently show focal glial differentiation, we now investigated 35 CPTs (19 males and 16 females 0.3-70 years old; median age, 25.0 years), including 21 choroid plexus papillomas (CPPs), 5 atypical CPP, and 9 choroid plexus carcinomas regarding their expression of the excitatory amino acid transporter-1 (EAAT1, corresponding to rodent GLAST/GLAST-1) by immunohistochemistry. In addition, 77 metastatic carcinomas, including 64 adenocarcinomas with mostly papillary formations, derived from different organs were examined. Of the 35 CPTs, 23 (66%) showed membranous EAAT1 expression in variable numbers of tumor cells, including all atypical CPP and 3 of 9 choroid plexus carcinomas (33%). None of the metastatic carcinomas showed membranous immunostaining. Excitatory amino acid transporter-1 expression in CPT was significantly age dependent (P < .0001), with the proportion of EAAT1-positive tumor cells increasing with age, but not sex dependent. There was a highly significant difference between EAAT1 expression in CPT and in metastatic carcinomas (P < .0001). Establishing a cutoff value of 1% immunoreactive tumor cells served in adult cases to distinguish CPT from metastatic adenocarcinomas with 100% specificity and 70% sensitivity and was associated with positive and negative predictive values of 100% and 91%, respectively. Our findings indicate that EAAT1 immunohistochemistry may be useful in differentiating CPT from metastatic carcinomas.
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PMID:Choroid plexus tumors differ from metastatic carcinomas by expression of the excitatory amino acid transporter-1. 1678 85

Previous studies have demonstrated that not only the benefits but also the toxicities of chemotherapy can be predicted by cDNA microarray analysis of tumor specimens obtained before chemotherapy against non-small cell lung cancer (NSCLC). We conducted a study of cDNA microarray analysis to determine whether the gene expression in peripheral blood taken from patients prior to chemotherapy were correlated with the outcome of chemotherapy with paclitaxel (Pac) and irinotecan (CPT) against advanced NSCLC. Thirty-one patients with stage IIIB or IV NSCLC were treated with CPT at 60 mg/m2 and Pac at 160 mg/m2 every 2 weeks. Seventeen of 31 patients achieved PR and the overall RR was 54.8%. The median survival time was 426 days and the 1-year survival rate was 58.1%. The expression levels of 1176 genes were analyzed in 31 patients with the AtlasTM Human Cancer 1.2 Array. Stepwise multivariate analysis revealed that the genes encoding protein phosphatase, IL-1alpha and IgA were independent predictive factors for chemosensitivity. Stepwise regression analysis revealed that the thyrotropin-releasing hormone receptor and alkylation repair genes were independent prognostic factors. In conclusion, the expression of certain genes was able to predict the benefits of this Pac and CPT chemotherapy regimen.
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PMID:Genome-wide cDNA microarray screening of genes related to the benefits of paclitaxel and irinotecan chemotherapy in patients with advanced non-small cell lung cancer. 1722 24

A 78-year-old patient had abdominal bloating since October 2002, and visited a GP, who noticed ascites, and referred the patient to our hospital. An exploratory laparotomy was performed and stage IIIc ovarian cancer was diagnosed. Six courses of docetaxel-carboplatin (DJ) chemotherapy were administered; however, the lesion was assessed as progressive disease (PD), and 24 courses of weekly paclitaxel were then administered. During the follow-up as an outpatient, a tumor marker increased again. Weekly paclitaxel was not effective this time, and the lesion was assessed as PD. The patient therefore received treatment with irinotecan and cisplatin (CPT-11+CDDP). These drugs have different mechanisms of action. The CA 125 level returned to normal following four courses of CPT-11+CDDP. The patient received a total of six courses, and thus far, no obvious recurrent lesion has been observed. These results suggest that CPT-11+CDDP may be effective against recurrent ovarian cancer, which is difficult to treat due to its resistance to platinum drugs and taxane drugs.
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PMID:[A recurrent ovarian cancer patient who achieved a complete response following irinotecan plus CDDP therapy]. 1735 44

We treated two patients in whom irinotecan (CPT-11)+cisplatin (CDDP) and irradiation showed efficacy against brain metastases of gastric cancer. CPT-11 and CDDP were administered on days 1 and 15 of a 28-day cycle at 60 mg/m(2) and 30 mg/m(2), respectively. The first patient was a 63-year-old man,who complained of headache and weakness. In March 2003, he was diagnosed as having Stage IV gastric cancer with peritoneal dissemination (T3, Nx, P1) and underwent total gastrectomy with D1 dissection. Chemotherapy with S-1 was continued after surgery. Two years and two months later, a metastatic tumor was found in the upper lobe of the right lung. The protocol was changed to S-1+CDDP, but progression of his disease occurred. The weekly paclitaxel (PTX) therapy was tried instead. Seven months later, he developed headache and weakness, and multiple brain metastases were diagnosed by CT scanning. We performed total brain irradiation (30 Gy) and started CPT-11+CDDP therapy, which was continued on a fortnightly basis at 60 mg/m(2) and 30 mg/m(2), respectively. The brain metastases regressed (PR), and this therapy led to a marked improvement in his quality of life. The second patient was a 78-year-old man, who complained of weakness of the lower extremities and dizziness. In November 2003, he was diagnosed as having stage IB gastric cancer (T2 (ss), N0, P0), and underwent total gastrectomy and splenectomy with D2 dissection. One year and four months later, local recurrence at the anastomosis was detected, as well as a metastatic tumor in the right lung. S-1, S-1+CDDP, and weekly PTX therapy were all tried. One year later, the patient was admitted with weakness and dizziness,and brain metastases were detected by CT scanning. We then performed Cyber Knife treatment and administered CPT-11+CDDP. As a result, his brain metastases partially regressed (PR).
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PMID:[Irinotecan+cisplatin and irradiation are effective for brain metastases of gastric cancer--two case reports]. 1763 47


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