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

The ability to induce apoptosis in tumor cells is critical to elicit a positive response to cytotoxic chemo-therapy. In this study, we investigated the effect of the topoisomerase I inhibitors camptothecin and SN-38, known to cause an unusual form of DNA damage, on apoptotic pathways using the leukemic cell line HL-60 and its vincristine-resistant variant HL-60 VCR. Both camptothecin and SN-38 induced high levels of apoptosis in sensitive cells when compared to the multidrug-resistant ones. Interestingly, a higher BCL-2/BAX ratio was observed in HL-60 VCR at the basal state and during treatments. Moreover, these cells which did not exhibit Bcr-abl translocation or bcrp efflux pump, overexpressed topoisomerase I protein. The data provide evidence that BCL-2 protein could protect HL-60 VCR from mitochondrial membrane depolarization and block ROS production in these cells. Finally, our results suggest that dysregulation of proteins associated with DNA replication and apoptotic process could contribute to the multidrug-resistance phenotype.
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PMID:From molecular characteristics to cellular events in apoptosis-resistant HL-60 cells. 1570 42

Members of the multidrug resistance-associated protein (MRP) family of transporters are believed to contribute to cytotoxic drug resistance and chemotherapy failure. We observed frequent MRP4 overexpression in aggressive primary neuroblastoma, a disease for which we have previously shown MRP1 to be a prognostic indicator. High MRP4 expression correlated with MYCN oncogene amplification and was significantly associated with poor clinical outcome. Although MRP4 is known to transport some nucleoside analogues, it has not previously been associated with resistance to drugs used to treat solid tumors. We now show that it mediates substantial resistance in vitro to the topoisomerase I poison irinotecan/CPT-11 and its active metabolite SN-38. These results suggest that MRP4 will be a useful prognostic marker for neuroblastoma and that clinical trials of irinotecan as a neuroblastoma treatment should monitor MRP4 expression. The same may be true for other tumor types expressing high levels of the transporter.
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PMID:Expression of multidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro. 1582 27

The combination of methylselenocysteine and irinotecan (CPT-11) is synergistic against FaDu and A253 xenografts. Methylselenocysteine/CPT-11 increased tumor cure rate to 100% in FaDu and to 60% in A253. In this study, the effect of methylselenocysteine on pharmacokinetic and pharmacogenetic profiles of genes relevant to CPT-11 metabolic pathway was evaluated to identify possible mechanisms associated with the observed combinational synergy. Nude mice bearing tumors (FaDu and A253) were treated with methylselenocysteine, CPT-11, and a combination of methylselenocysteine/CPT-11. Samples were collected and analyzed for plasma and intratumor concentration of CPT-11 and 7-ethyl-10-hydroxyl-camptothecin (SN-38) by high-performance liquid chromatography. The intratumor relative expression of genes related to the CPT-11 metabolic pathway was measured by real-time PCR. After methylselenocysteine treatment, the intratumor area under the concentration-time curve of SN-38 increased to a significantly higher level in A253 than in FaDu and was associated with increased expression of CES1 in both tumors. Methylselenocysteine/CPT-11 treatment, compared with CPT-11 alone, resulted in a significant decrease in levels of ABCC1 and DRG1 in FaDu tumors and an increase in levels of CYP3A5 and TNFSF6 in A253 tumors. No statistically significant changes induced by methylselenocysteine/CPT-11 were observed in the levels of other investigated variables. In conclusion, the significant increase in the cure rate after methylselenocysteine/CPT-11 could be related to increased drug delivery into both tumors (CES1), reduced resistance to SN-38 (ABCC1 and DRG1) in FaDu, and induced Fas ligand apoptosis (TNFSF6) in A253. No correlation was observed between cure rate and other investigated variables (transporters, degradation enzymes, DNA repair, and cell survival/death genes) in either tumor.
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PMID:Irinotecan pharmacokinetic and pharmacogenomic alterations induced by methylselenocysteine in human head and neck xenograft tumors. 1589 49

A series of hexacyclic camptothecin derivatives were synthesized to test for antitumor activity as topoisomerase I inhibitor. The strategy of synthesis was used for the formation of additional furan and dihydrofuran rings fused with 9- and 10-positions of camptothecin. All of the hexacyclic camptothecins were assayed for cytotoxicity against four human tumor cell lines, HL60, BEL-7402, HCT-116, and HeLa, and showed very impressive cytotoxicity activity in vitro. Enzyme activity of the hexacyclic camptothecins was evaluated, being equal or superior to that of SN-38. The stability of four compounds was assessed in human plasma. Two of these compounds were chosen to test for antitumor activity in vivo against Sarcoma-180. The results suggested that additional furan and dihydrofuran rings could improve the antitumor activity in vitro and vivo, though the stability of the lactone ring did not increase.
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PMID:Synthesis and antitumor activity of the hexacyclic camptothecin derivatives. 1591 96

Our objective was to evaluate in vitro and in vivo the effect of the combination of trabectedin (Yondelis, ET-743) and irinotecan (CPT-11) or its major metabolite SN-38 in a human rhabdomyosarcoma cell line. The schedule trabectedin (1 h) followed by irinotecan or SN-38 (24 h) and the opposite sequence (irinotecan or SN-38 24 h followed by trabectedin 1 h) were analyzed in a rhabdomyosarcoma cell line. In vivo studies were conducted with trabectedin and irinotecan at the doses of 0.2 and 20 mg/kg, respectively, simultaneously administered with a q4d x 3 schedule. In vitro studies indicated an overall additive effect [combination index (CI) relatively close to 1.0], with the former schedule slightly superior to the latter (at the IC50 effect levels: CI=0.89 versus 1.07). Neither transcription nor expression of DNA topoisomerase I was affected by trabectedin treatment. In vivo the therapeutic results of the combination were certainly more impressive: trabectedin and irinotecan combination caused a strong and long-lasting effect on tumor growth (tumor volume inhibition=89%, log10 cell kill=1.6), whereas each drug given as a single agent was only marginally active. The discrepancy between the in vitro and in vivo results suggests possible mechanisms involving host cells, other than tumor cells. The striking effects of the combination observed in vivo could be related to a combination of a direct cytotoxic and an anti-inflammatory indirect effect. The very marked and long-lasting effect of the trabectedin and irinotecan combination in vivo suggests a basis for a clinical evaluation in pediatric patients with rhabdomyosarcoma.
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PMID:Combination of trabectedin and irinotecan is highly effective in a human rhabdomyosarcoma xenograft. 1609 28

We have performed in vitro incubations of blood from male and female volunteers, smokers and non-smokers, with irinotecan at a gradient of different concentrations in order to investigate changes of partition between red blood cells (RBCs), total plasma and the free fraction. Since irinotecan (CPT-11) is not metabolized in vitro, there is no data available on its active metabolite SN-38. After extraction and sample pre-treatment, a validated high-performance liquid chromatography method followed by fluorescence detection was used to determine the concentration of the drug in the different blood constituents. The partition ratio [the concentration in the erythrocytes divided by the concentration in plasma (E/P)] was calculated. The partition ratio of CPT-11 varied from 0.7 to 2.8, reflecting its relatively high affinity for the erythrocyte, probably because of its only moderate plasma protein binding (65%). The partition ratios increased significantly with higher whole-blood concentrations, favoring uptake in the erythrocytes when plasma protein binding is saturated. No gender difference was detected, but we found relatively more CPT-11 in the erythrocytes of non-smokers compared to smokers. The incorporation of drugs into the RBC pool may be important for transportation to tumor tissue and efficacy. Smoking can have a significant influence on drug partition in the blood.
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PMID:In vitro partition of irinotecan (CPT-11) in human volunteer blood: the influence of concentration, gender and smoking. 1609 39

Multidrug resistance protein 1 (MRP1) is an ATP-binding cassette transporter that confers multidrug resistance on tumor cells. Much convincing evidence has accumulated that MRP1 transports most substances in a GSH-dependent manner. On the other hand, several reports have revealed that MRP1 can transport some substrates independently of GSH; however, the importance of GSH-independent transport activity is not well established and the mechanistic differences between GSH-dependent and -independent transport by MRP1 are unclear. We previously demonstrated that the amino acids W261 and K267 in the L0 region of MRP1 were important for leukotriene C4 (LTC4) transport activity of MRP1 and for GSH-dependent photolabeling of MRP1 with azidophenyl agosterol-A (azidoAG-A). In this paper, we further tested the effect of W222L, W223L and R230A mutations in MRP1, designated dmL0MRP1, on MRP1 transport activity. SN-38 is an active metabolic form of CPT-11 that is one of the most promising anti-cancer drugs. Membrane vesicles prepared from cells expressing dmL0MRP1 could transport SN-38, but not LTC4 or estradiol-17 (beta-D-glucuronate), and could not be photolabeled with azidoAG-A. These data suggested that SN-38 was transported by a different mechanism than that of GSH-dependent transport. Understanding the GSH-independent transport mechanism of MRP1, and identification of drugs that are transported by this mechanism, will be critical for combating MRP1-mediated drug resistance. We performed a pairwise comparison of compounds that are transported by MRP1 in a GSH-dependent or -independent manner. These data indicated that it may be possible to predict compounds that are transported by MRP1 in a GSH-independent manner.
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PMID:MRP1 mutated in the L0 region transports SN-38 but not leukotriene C4 or estradiol-17 (beta-D-glucuronate). 1609 82

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

Until recently, the use of Se-methylselenocysteine (MSC) as selective modulator of the antitumor activity and selectivity of anticancer drugs including irinotecan, a topoisomerase I poison, had not been evaluated. Therapeutic synergy between MSC and irinotecan was demonstrated by our laboratory in mice bearing human squamous cell carcinoma of the head and neck tumors. In FaDu xenografts, a poorly differentiated tumor-expressing mutant p53, the cure rate was increased from 30% with irinotecan alone to 100% with the combination of irinotecan and MSC. Cellular exposure to cytotoxic concentration of SN-38, the active metabolite of irinotecan (0.1 microM) alone and in combination with noncytotoxic concentration of MSC (10 microM) did not result in additional enhancement of chk2 phosphorylation and downregulation of specific DNA replication-associated proteins, cdc6, MCM2, cdc25A, nor increase in PARP cleavage, caspase activation and the 30-300 kb DNA fragmentation induced by SN-38 treatment. MSC did not alter significantly markers associated with apoptosis, nor potentiate irinotecan-induced apoptosis. These results indicate that apoptosis is unlikely to be one of the main mechanism associated with the observed in vivo therapeutic synergy. In contrast, significant downregulation of cyclooxygenase-2 (COX-2) expression and activity was observed in the cells exposed to SN-38 in combination with MSC compared to SN-38 alone. Moreover, the inhibition of PGE(2) production was also observed in the cells treated with the combination as compared with SN-38 alone. Analysis of tumor tissues at 24 h after treatment with synergistic modality of irinotecan and MSC revealed significant downregulation of COX-2, inducible nitric oxide synthase (iNOS) and hypoxia-induced factor-1alpha expression (HIF 1alpha). Moreover, decreased microvessel density was observed after irinotecan treatment with the addition of MSC. These results suggest that observed therapeutic synergy correlates with the inhibition of neoangiogenesis through the downregulation of COX-2, iNOS and HIF-1alpha expression.
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PMID:Potentiation of irinotecan sensitivity by Se-methylselenocysteine in an in vivo tumor model is associated with downregulation of cyclooxygenase-2, inducible nitric oxide synthase, and hypoxia-inducible factor 1alpha expression, resulting in reduced angiogenesis. 1651 18

EGFR mutations are a major determinant of lung tumor response to gefitinib, an EGFR-specific tyrosine kinase inhibitor. Obtaining a response from lung tumors expressing wild-type EGFR is a major obstacle. The combination of gefitinib and cytotoxic drugs is one strategy against lung cancers expressing wild-type EGFR. The DNA topoisomerase inhibitor irinotecan sulfate (CPT-11) is active against lung cancer. We examined the sensitivity of lung cancers expressing wild- or mutant-type EGFR to the combination of gefitinib and CPT-11. The in vitro effect of gefitinib and SN-38 (the active metabolite of CPT-11) was examined in seven lung cancer cell lines using the dye formation assay with a combination index. When administered concurrently, gefitinib and SN-38 had a synergistic effect in five of the seven cell lines expressing wild-type EGFR, whereas the combination was antagonistic in PC-9 cells and a PC-9 subline resistant to gefitinib and expressing deletional mutant EGFR (PC-9/ZD). When administered sequentially, treatment with SN-38 followed by gefitinib had remarkable synergistic effects in the PC-9 and PC-9/ZD cells. In an in vivo tumor-bearing model, this combination had a schedule-dependent synergistic effect in the PC-9 and PC-9/ZD cells. An immunohistochemical analysis of the tumors in mice treated with CPT-11 and gefitinib demonstrated that the number of Ki-67 positive tumor cells induced by CPT-11 treatment was decreased when CPT-11 was administered in combination with gefitinib. In conclusion, the sequential combination of CPT-11 and gefitinib is considered to be active against lung cancer.
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PMID:Effects of different combinations of gefitinib and irinotecan in lung cancer cell lines expressing wild or deletional EGFR. 1671 12


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