Cancer Chemotherapy and Pharmacology (CANCER CHEMOTH PHARM)

Publications in this journal

• Article: A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients

  Jeannine S. McCune, Erica L. Woodahl, Terry Furlong, Barry Storer, Joanne Wang, Shelly Heimfeld, H. Joachim Deeg, Paul V. O’Donnell
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  ABSTRACT: PurposeSixteen patients diagnosed with various hematologic malignancies participated in a phase II study evaluating the addition of rabbit antithymocyte globulin (rATG, Thymoglobulin®) to the hematopoietic cell transplant (HCT) conditioning regimen of IV fludarabine monophosphate (fludarabine) and targeted intravenous (IV) busulfan (fludarabine/Tbusulfan). Our goal was to evaluate pharmacologic biomarkers pertinent to both medications in these patients. MethodsWe characterized the interpatient variability of pharmacologic biomarkers relevant to busulfan, specifically busulfan concentration at steady state, and fludarabine, specifically F-ara-A area under the curve (AUC) and fludarabine triphosphate (F-ara-ATP) intracellular accumulation and concentration in separate CD4+ and CD8+ T-lymphocyte populations. ResultsAcute and chronic graft versus host disease (GvHD) occurred in 11 patients and one patient, respectively. Four patients died before day +100 of non-relapse causes, which met the protocol stopping guidelines. The cumulative incidence of relapse was 25% at 3year post-HCT. Interpatient variability in the busulfan- and fludarabine-relevant pharmacologic biomarkers was 2.1- to 2.5-fold. F-ara-A AUC and accumulated F-ara-ATP in CD8+ cells had the highest hazard ratio for non-relapse mortality and overall survival, respectively. However, neither achieved statistical significance. ConclusionsThe low rates of GvHD, particularly in its chronic form, were encouraging, and further biomarker studies are warranted to optimize the fludarabine/Tbusulfan/rATG conditioning regimen. KeywordsBusulfan–Fludarabine–Hematopoietic cell transplant–Biomarkers–Therapeutic drug monitoring–Pharmacokinetics
  Cancer Chemotherapy and Pharmacology 04/2012; 69(1):263-272.
• Article: Synergistic interactions between peloruside A and other microtubule-stabilizing and destabilizing agents in cultured human ovarian carcinoma cells and murine T cells

  Anja Wilmes, David O’Sullivan, Ariane Chan, Clarissa Chandrahasen, Ian Paterson, Peter T. Northcote, Anne Camille La Flamme, John H. Miller
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  ABSTRACT: PurposeMicrotubule-stabilizing agents are an important class of anticancer compounds. Peloruside A and laulimalide bind to a different site on the microtubule to taxoid site drugs such as paclitaxel (Taxol®), docetaxel (Taxotere®), ixabepilone (Ixempra®), the epothilones, and discodermolide. The purpose of this study was to examine the synergistic interactions of these drugs when given in combination in relation to the differences in their binding sites on the microtubule. MethodsHuman ovarian carcinoma cells (1A9 cells) and murine T cells were treated with different combinations of microtubule-stabilizing or destabilizing agents. The compounds were given individually and in combination, and the antiproliferative activity was assessed to calculate a combination index (CI) from the equation: CI=D 1/Dx 1+D 2/Dx 2 in which D 1 and D 2 are the concentrations of drug 1 and drug 2 that when given together give the same response as drug 1 and 2 alone (Dx 1 and Dx 2). Thus, a CI value of less than 1.0 indicates a synergistic effect between the two drugs in which the response to the two drugs given together is greater than the additive response of the two drugs if given on their own. ResultsAs anticipated from previous invitro studies, peloruside A and laulimalide did not synergize with each other. They also failed to synergize with the microtubule-destabilizing agents vinblastine and 2-methoxyestradiol. Peloruside A and laulimalide did, however, synergize with the epothilones, as had been previously shown, but not with docetaxel or discodermolide. ConclusionsCombining two microtubule-targeting agents with different binding sites does not guarantee a synergistic interaction in cells, and additional factors are likely to be involved. This study highlights the importance of preclinical testing of actual combinations of drugs before proceeding into clinical trials. KeywordsAnticancer drug–Combination therapy–Laulimalide–Microtubule-targeting agent–Peloruside A–Synergy
  Cancer Chemotherapy and Pharmacology 04/2012; 68(1):117-126.
• Article: Dose-finding study of docetaxel, oxaliplatin, and S-1 for patients with advanced gastric cancer

  Dae Young Zang, Dae Hyun Yang, Min-Jeong Kim, Kyung Mi Jang, Se Won Hwang, Kyo-Sang Yoo, Taeho Han, Ho Young Kim, Hyo Jung Kim, Jung Hye Kwon, Hun Ho Song, Sarah Park, Joo Young Jung, Hyeong Su Kim, Jung Han Kim
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  ABSTRACT: PurposeTo determine the maximum tolerated dose (MTD), recommended dose (RD), and activity of combined docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy on metastatic gastric cancer. Patients and methodsDocetaxel and oxaliplatin were administered intravenously on day 1 and S-1 was administered orally on days 1–14 of every 21-day cycle. The doses of docetaxel/oxaliplatin/S-1 in the phase I study were level −1A, 52.5/80/60mg/m2; level −1B, 52.5/80/80mg/m2; level 1A, 52.5/105/80mg/m2; level 1B, 52.5/130/80mg/m2; level 2A, 60/105/80mg/m2; level 2B, 60/130/80mg/m2; level 3A, 67.5/105/80mg/m2; level 3B, 67.5/130/80mg/m2; level 4A, 75/105/80mg/m2; level 4B, 75/130/80mg/m2. ResultsNine patients were enrolled. One of six patients at level 1A and two of three patients at level 1B developed dose-limiting toxicity (febrile neutropenia) during the initial two cycles. Therefore, the doses used at levels 1B and 1A were defined as the MTD and RD, respectively. All patients were evaluated for toxicity and response. Six partial responses were noted, and the overall response rate was 67%. ConclusionThe RD of the DOS regimen in patients with advanced gastric cancer was docetaxel 52.5mg/m2 and oxaliplatin 105mg/m2 on day 1 and S-1 80mg/m2 on days 1–14 of every 21-day cycle. A phase II study using the RD is currently underway.
  Cancer Chemotherapy and Pharmacology 04/2012; 64(5):877-883.
• Article: Impact of EGFR mutations on treatment of non-small cell lung cancer

  Bruce E. Johnson, David Jackman, Pasi A. Jänne
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  ABSTRACT: Somatic mutations in the epidermal growth factor receptor (EGFR) have been identified in advanced non-small cell lung cancer (NSCLC) patients who achieve dramatic clinical and radiographic responses to treatment with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Retrospective studies comparing outcomes of patients with and without EGFR mutations treated with EGFR-TKIs demonstrate that patients with EGFR mutations live significantly longer than those without mutations. In addition, patients with NSCLC and a somatic deletion mutation of exon 19 exhibit longer survival than patients with point mutations of exon 21. Secondary resistance mutations have also been identified. Patients exhibiting a somatic sensitizing mutation of EGFR who achieve partial response to gefitinib or erlotinib therapy eventually develop clinical resistance to treatment with EGFR-TKI. Approximately half of these resistant patients develop a detectable secondary acquired resistance mutation (T790M) in their tumor. New irreversible EGFR inhibitors have in vitro and in vivo evidence of antitumor activity against lung cancer cells harboring both the sensitizing and resistance mutations. These findings suggest that patients with advanced NSCLC bearing somatic EGFR mutations should receive treatment with an EGFR-TKI included as at least part of their initial therapy. Trials are starting to test the irreversible EGFR inhibitors in patients with NSCLC after they develop resistance to their initial treatment with gefitinib or erlotinib.
  Cancer Chemotherapy and Pharmacology 04/2012; 58:5-9.
• Article: Plasma pharmacokinetics and oral bioavailability of the 3,4,5,6-tetrahydrouridine (THU) prodrug, triacetyl-THU (taTHU), in mice

  Jan H. Beumer, Julie L. Eiseman, Judith A. Gilbert, Julianne L. Holleran, Archibong E. Yellow-Duke, Dana M. Clausen, David Z. D’Argenio, Matthew M. Ames, Pamela A. Hershberger, Robert A. Parise, Lihua Bai, Joseph M. Covey, Merrill J. Egorin
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  ABSTRACT: PurposeCytidine drugs, such as gemcitabine, undergo rapid catabolism and inactivation by cytidine deaminase (CD). 3,4,5,6-tetrahydrouridine (THU), a potent CD inhibitor, has been applied preclinically and clinically as a modulator of cytidine analogue metabolism. However, THU is only 20% orally bioavailable, which limits its preclinical evaluation and clinical use. Therefore, we characterized THU pharmacokinetics after the administration to mice of the more lipophilic pro-drug triacetyl-THU (taTHU). MethodsMice were dosed with 150mg/kg taTHU i.v. or p.o. Plasma and urine THU concentrations were quantitated with a validated LC–MS/MS assay. Plasma and urine pharmacokinetic parameters were calculated non-compartmentally and compartmentally. ResultstaTHU did not inhibit CD. THU, after 150mg/kg taTHU i.v., had a 235-min terminal half-life and produced plasma THU concentrations >1μg/mL, the concentration shown to inhibit CD, for 10h. Renal excretion accounted for 40–55% of the i.v. taTHU dose, 6–12% of the p.o. taTHU dose. A two-compartment model of taTHU generating THU fitted the i.v. taTHU data best. taTHU, at 150mg/kg p.o., produced a concentration versus time profile with a plateau of approximately 10μg/mL from 0.5–2h, followed by a decline with a 122-min half-life. Approximately 68% of i.v. taTHU is converted to THU. Approximately 30% of p.o. taTHU reaches the systemic circulation as THU. ConclusionsThe availability of THU after p.o. taTHU is 30%, when compared to the 20% achieved with p.o. THU. These data will support the clinical studies of taTHU. KeywordsTetrahydrouridine–THU–Bioavailability–Metabolism–Mouse–Cytidine deaminase
  Cancer Chemotherapy and Pharmacology 04/2012; 67(2):421-430.
• Article: Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model

  Terence O’Reilly, Heidi A. Lane, Jeanette M. Wood, Christian Schnell, Amanda Littlewood-Evans, Josef Brueggen, Paul M. J. McSheehy
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  ABSTRACT: PurposeEverolimus (RAD001, Afinitor) is an mTORC1 pathway inhibitor, and vatalanib (PTK/ZK) is a pan VEGF-R tyrosine kinase inhibitor (TKI). These two drugs have been shown to have overlapping but also distinct anti-angiogenic effects. Consequently, we investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of their combination in vivo. MethodsMurine melanoma B16/BL6 cells were grown orthotopically in BL6/C57 mice by injection into the derma of both ears to create a primary tumour which metastasized rapidly to the cervical lymph nodes. Mice were treated daily p.o. with PTK/ZK (100mg/kg) or everolimus (1mg/kg) or their combination, and anti-tumour efficacy (PD) assessed. In the same model, plasma PK of everolimus was measured following single doses of the monotherapy or combination schedules. ResultsTwo independent experiments showed that combination of everolimus and PTK/ZK caused at least additive increases in anti-tumour activity compared to either monotherapy, without increases in toxicity. Pooling the data to improve the statistical power demonstrated the interactions to be synergistic. PK modelling showed that although PTK/ZK increased everolimus plasma concentrations by about twofold, this PK drug–drug interaction could not account for the increased anti-tumour effect of the combination. Modelling of the PTK/ZK dose–response curve in this model suggested that any effect of everolimus on the PK of PTK/ZK was unlikely to affect efficacy. Measurement of changes in tumour and plasma VEGF levels at the endpoint of therapy confirmed earlier observations of differential effects of these two agents. ConclusionsThe combination of everolimus and PTK/ZK hold promise for the treatment of human cancers. KeywordsEverolimus–PTK/ZK–PK-PD–VEGF-R TKI–mTOR–Anti-tumour activity–Angiogenesis
  Cancer Chemotherapy and Pharmacology 04/2012; 67(1):193-200.
• Article: Pyrrolotetrazinones deazaanalogues of temozolomide induce apoptosis in Jurkat cell line: involvement of tubulin polymerization inhibition

  Giampietro Viola, Laura Cecconet, Anna Leszl, Giuseppe Basso, Paola Brun, Alessia Salvador, Francesco Dall’Acqua, Patrizia Diana, Paola Barraja, Girolamo Cirrincione
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  ABSTRACT: PurposePyrrolotetrazinones are a new class of azolotetrazinones endowed with a high, remarkable antiproliferative activity in human tumor cultured cells. They hold the deaza skeleton of the antitumor drug temozolomide, although preliminary investigations indicated a different mechanism of action. To understand their mechanism(s) of action along with their target at molecular level, four derivatives were selected on the basis of their activity on a panel of human tumor cell lines and they were investigated in depth in a T leukemia cell line (Jurkat). Methods and resultsFlow cytometric analysis of cell cycle after treatment with pyrrolotetrazinones has demonstrated that they were able to induce an arrest of the cell cycle in G2/M phase. This effect was accompanied by apoptosis of the treated cells which is further characterized by exposure of phosphatidylserine on the external surface of the cell membranes. Mitochondria were strongly involved in the apoptotic pathway as demonstrated by the induced mitochondrial depolarization, generation of reactive oxygen species, and activation of caspase-3. Western blot analysis showed that Bcl-2 expression was down regulated whereas the proapototic protein Bax was upregulated in a time dependent manner. Moreover, these compounds induced a clear increase in the mitotic index, and inhibited microtubule assembly in vitro indicating that pyrrolotetrazinones, at variance with temozolomide, involved an efficacious inhibition of tubulin polymerization in their mechanism of action. Interestingly compound 3 at the concentration of 50mg/kg body weight significantly inhibited in vivo the growth of a syngeneic hepatocellular carcinoma in Balb/c mice. ConclusionThese results suggest that pyrrolotetrazinones inhibit microtubule polymerization, induce G2/M arrest of cell cycle and cause apoptosis through the mitochondrial pathway identifying them as novel effective antimitotic agents with potential for clinical development.
  Cancer Chemotherapy and Pharmacology 04/2012; 64(6):1235-1251.
• Article: The glutathione S-transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol overcomes the MDR1-P-glycoprotein and MRP1-mediated multidrug resistance in acute myeloid leukemia cells

  Alessandro Ascione, Maurizio Cianfriglia, Maria Luisa Dupuis, Alessandra Mallano, Andrea Sau, Francesca Pellizzari Tregno, Silvia Pezzola, Anna Maria Caccuri
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  ABSTRACT: PurposeThere has been an ever growing interest in the search for new anti-tumor compounds that do not interact with MDR1-Pgp and MRP1 drug transporters and so circumvent the effect of these proteins conferring multidrug resistance (MDR) and poor prognosis in AML patients. We have investigated the cytotoxic activity of the strong glutathione S-transferase (GST) inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) on AML (HL60) cell lines. MethodsFunctional drug efflux studies and cell proliferation assays were performed on both sensitive and MDR AML (HL60) cells after incubation with NBDHEX. Moreover, the mode of cell death (apoptosis vs. necrosis) as well as the correlation between NBDHEX susceptibility and GST activity or Bcl-2 expression was investigated. ResultsNBDHEX is not a substrate of either MDR1-Pgp or MRP1 efflux pumps; in fact, it is not only cytotoxic toward the parental HL60 cell line, but also overcomes the MDR phenotype of its HL60/DNR and HL60/ADR variants. ConclusionsThe data herein reported show that NBDHEX mediates efficient killing of both MDR1-Pgp and MRP1 over-expressing AML cells. Therefore, this drug can potentially be used as an effective agent for treating MDR in AML patients.
  Cancer Chemotherapy and Pharmacology 04/2012; 64(2):419-424.
• Article: Can the 2-13C-uracil breath test be used to predict the effect of the antitumor drug S-1?

  Yukimoto Ishii, Shigeru Suzuki, Yasuo Takahashi, Tadatoshi Takayama, Satoshi Asai
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  ABSTRACT: PurposeS-1 is an oral anticancer drug containing tegafur (FT), a pro-drug of fluorouracil, combined with two modulators, 5-chloro-2,4-dihydroxypyridine and potassium oxonate (Oxo), at a molar ratio of 1:0.4:1. CYP2A6 genetic polymorphism and dihydropyrimidine dehydrogenase (DPD) inhibition are important for the antitumor effect of S-1. Exploiting the usefulness of the 2-13C-uracil breath test (UrBT) as an indicator of DPD activity, we examined whether the results of CYP2A6 genetic polymorphism analysis and UrBT could be used to predict the antitumor effect of S-1. MethodsThirty-four patients with advanced or recurrent cancer (15, 16 and 3 with gastric, colorectal and pancreatic cancer, respectively) were orally administered 40mg/m2 S-1 twice daily in the morning and evening. Eighteen patients with a complete response (CR)/partial response (PR) (2 with CR, 16 with PR) and 16 with progressive disease (PD) were compared with respect to CYP2A6 genetic polymorphisms (1- vs. 2-allele mutation), UrBT results, and plasma FT and 5-fluorouracil levels at 3h after S-1 ingestion in the morning. ResultsOn multivariate analysis between the CR/PR and PD groups, only the UrBT results was an independent factor of CR/PR to S-1 (95% CI 1.02–1.10). ConclusionThese results suggest that the anticancer effect of S-1 can be predicted by performing UrBT 3h after the initial oral S-1 administration. KeywordsS-1-CYP2A6-Uracil- 13C-Breath test
  Cancer Chemotherapy and Pharmacology 04/2012; 66(2):333-343.
• Article: Pharmacokinetics and tissue distribution of Kendine 91, a novel histone deacetylase inhibitor, in mice

  Dorleta Otaegui, Alicia Rodríguez-Gascón, Aizpea Zubia, Fernando P. Cossío, José Luis Pedraz
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  ABSTRACT: PurposeThe present investigation was undertaken to characterize the pharmacokinetics and oral bioavailability of Kendine 91 in mice and to compare it with other HDAC (histone deacetylases) inhibitors. MethodsAfter administration of a single intravenous dose (10mg/kg) or a single oral dose (50mg/kg) blood and tissues samples were collected and analysed by HPLC/MS/MS. ResultsElimination half-life was higher than that of SAHA (5.87 vs. 0.38h after intravenous (IV) administration and 10.29 versus 0.75h after oral administration). Absolute oral bioavailability was found to be 18%. Total body clearance (7.72l/h/kg) was greater than the hepatic blood flow of 5.4l/h/kg in mice and larger than glomerular filtration rate in mice (0.84l/h/kg). Tissue levels and distribution volume indicate a high capacity of Kendine 91 to distribute into tissues. ConclusionsThis preliminary pharmacokinetic evaluation prompts us to believe that it is worth pursuing further development of Kendine 91 as an anticancer drug.
  Cancer Chemotherapy and Pharmacology 04/2012; 64(1):153-159.
• Article: TP53 codon 72 polymorphism associated with prognosis in patients with advanced gastric cancer treated with paclitaxel and cisplatin

  Jong Gwang Kim, Sang Kyun Sohn, Yee Soo Chae, Hong Suk Song, Ki-Young Kwon, Young Rok Do, Min Kyoung Kim, Kyung Hee Lee, Myung Soo Hyun, Won Sik Lee, Chang-Hak Sohn, Joo Seop Jung, Gab Chul Kim, Ho Young Chung, Wansik Yu
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  ABSTRACT: PurposeThe present study analyzed the polymorphisms of apoptosis-related genes and their impact on the response to chemotherapy and PurposeThe present study analyzed the polymorphisms of apoptosis-related genes and their impact on the response to chemotherapy and survival of patients with advanced gastric cancer. survival of patients with advanced gastric cancer. Patients and methodsFifty-seven patients with advanced gastric cancer treated with paclitaxel and cisplatin combination chemotherapy were enrolled Patients and methodsFifty-seven patients with advanced gastric cancer treated with paclitaxel and cisplatin combination chemotherapy were enrolled in the present study. The genomic DNA was extracted from paraffin-embedded tissue, and the single nucleotide polymorphisms in the present study. The genomic DNA was extracted from paraffin-embedded tissue, and the single nucleotide polymorphisms (SNPs) of ten apoptosis-related genes [LTA, TP53, BCL2L11, BID, FASL, caspase 3, caspase 6, caspase 7, and caspase 9] determined (SNPs) of ten apoptosis-related genes [LTA, TP53, BCL2L11, BID, FASL, caspase 3, caspase 6, caspase 7, and caspase 9] determined using a polymerase chain reaction–restriction fragment length polymorphism assay. using a polymerase chain reaction–restriction fragment length polymorphism assay. ResultsThe Arg/Pro and Pro/Pro genotypes of TP53 codon 72 were significantly correlated with a lower response rate to the combination ResultsThe Arg/Pro and Pro/Pro genotypes of TP53 codon 72 were significantly correlated with a lower response rate to the combination chemotherapy when compared to the Arg/Arg genotype (35.7 vs. 66.7%, P-value 0.019) in a logistic regression analysis. A multivariate survival analysis also showed that the time to progression chemotherapy when compared to the Arg/Arg genotype (35.7 vs. 66.7%, P-value 0.019) in a logistic regression analysis. A multivariate survival analysis also showed that the time to progression for the patients with the Arg/Pro and Pro/Pro genotypes of TP53 codon 72 was worse than for the patients with the Arg/Arg for the patients with the Arg/Pro and Pro/Pro genotypes of TP53 codon 72 was worse than for the patients with the Arg/Arg genotype (Hazard ratio=3.056, P-value=0.047), whereas the overall survival was not significantly different. genotype (Hazard ratio=3.056, P-value=0.047), whereas the overall survival was not significantly different. ConclusionThe TP53 codon 72 SNP was found to be predictive of the response to chemotherapy and correlate with the time to progression ConclusionThe TP53 codon 72 SNP was found to be predictive of the response to chemotherapy and correlate with the time to progression in patients with advanced gastric cancer treated with paclitaxel and cisplatin chemotherapy. in patients with advanced gastric cancer treated with paclitaxel and cisplatin chemotherapy.
  Cancer Chemotherapy and Pharmacology 04/2012; 64(2):355-360.
• Article: Docetaxel pharmacokinetics and its correlation with two in vivo probes for cytochrome P450 enzymes: the C14-erythromycin breath test and the antipyrine clearance test

  M. Michael, C. Cullinane, A. Hatzimihalis, C. O’Kane, A. Milner, R. Booth, S. Schlicht, S. J. Clarke, P. Francis
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  ABSTRACT: BackgroundDocetaxel has marked inter-patient PK variability, and metabolic phenotypic probes may enable individualised dosing. This is the first report directly comparing the erythromycin breath test (EBT) (a CYP3A4 probe) with the antipyrine clearance test (ACT), (a general CYP-P450/predominant CYP3A4 probe) for the correlation with docetaxel PK and toxicity. MethodsPatients pretherapy underwent: (A) EBT: IV C14[N-methyl]-erythromycin was administered and breath samples analysed for 14CO2, derived parameters included (1) 14CO2 flux at 10-min (CO2f10), (2) 20-min (CO2f20), (3) terminal rate constant kCO2 and (4) AUCCO2,(0–∞) and AUCCO2,(0–60). (B) ACL test: patients were given oral antipyrine 10mg/kg, blood samples were taken for PK, and the clearance (CLAnt) was derived. Docetaxel was then given at 75mg/m2/3-weekly or 35mg/m2/weekly. Samples taken for docetaxel PK in first course on day 1 and PK parameters included clearance (CLDoc). ResultsTwenty patients accrued, docetaxel: 3-weekly/weekly=13:7. EBT parameters (N=19) (mean, [CV%]): CO2f10 (%/min) 0.051 (106), CO2f20 0.052 (82), kCO2 (min−1) 0.007 (22), AUCCO2,(0–∞) 7.9 (85), AUCCO2,(0–60) 2.64 (81). CLAnt (N=19) (ml/min); 35.8 (37). Docetaxel PK parameters (N=19): CLDoc (l/h)=57.2 (36), tDoc1/2 (h)=12.7 (33). No correlations were observed between the docetaxel PK and EBT parameters. For docetaxel weekly patients, a significant linear relationship was observed between CLDoc and CLAnt (P=0.007, R 2=79.47%). ConclusionsThe utility of EBT for the prediction of docetaxel PK was not confirmed in this study. The antipyrine clearance test may be superior in this regard for docetaxel, but regimen dependent and hence warrants further evaluation. KeywordsDocetaxel–In vivo probes–Erythromycin breath test–Antipyrine
  Cancer Chemotherapy and Pharmacology 04/2012; 69(1):125-135.
• Article: In response to Dr. Han’s comments

  Mattheos Bobos, Aristotelis Bamias
  Cancer Chemotherapy and Pharmacology 04/2012; 67(1):245-245.
• Article: Cytokeratin 8/18 monoclonal antibody was dissimilar to anti-cytokeratin CAM 5.2

  Shao-Chuan Wang, Fong-Lin Chen, Wea-Lung Lin, Po-Hui Wang, Chih-Ping Han
  Cancer Chemotherapy and Pharmacology 04/2012; 67(1):243-244.
• Article: Inhibition of N-linked glycosylation by tunicamycin induces E-cadherin-mediated cell–cell adhesion and inhibits cell proliferation in undifferentiated human colon cancer cells

  Julio Cesar Madureira de Freitas Junior, Bárbara Du Rocher D’Aguiar Silva, Waldemir Fernandes de Souza, Wallace Martins de Araújo, Eliana Saul Furquim Werneck Abdelhay, José Andrés Morgado-Díaz
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  ABSTRACT: PurposeAberrant protein glycosylation and disassembly of E-cadherin-mediated cell–cell adhesion are characteristics of epithelial cancer. However, the relationship between these two events in colorectal cancer remains to be defined. In this study, we analyzed whether N-glycan expression is crucial for the loss of E-cadherin-mediated cell–cell adhesion in human colorectal cancer cells. MethodsDifferentiated Caco-2 and undifferentiated HCT-116 colon cancer cells were used as models of stable and unstable adherens junctions (AJs), respectively. Complex-type N-glycans were detected using the lectins E-PHA (Phaseolus vulgaris E.) and L-PHA (Phaseolus vulgaris L.). To study E-cadherin-mediated AJ assembly, we examined the effects of swainsonine, an inhibitor of α-mannosidase II, and tunicamycin, a drug that inhibits the biosynthesis of N-glycans, via western blot, immunofluorescence, differential extraction in Triton X-100, and electron microscopy. Cell proliferation and apoptosis were examined by crystal violet staining and flow cytometry, respectively. ResultsWe observed positive labeling for E-PHA and L-PHA lectins in both cell lines; however, HCT-116 cells had increased E-cadherin-linked complex-type N-glycans. Interestingly, tunicamycin, but not swainsonine, was able to induce functional E-cadherin-mediated cell–cell adhesion in undifferentiated HCT-116 cells, as shown by the increased association of E-cadherin with the actin cytoskeleton. Moreover, in HCT-116 cells, tunicamycin also induced the formation of tight cell–cell contacts, and it inhibited cell proliferation without triggering apoptosis. ConclusionsCollectively, our results demonstrate for the first time that altered N-glycan expression plays an important role in the loss of AJ stability in undifferentiated colorectal cancer cells and that this loss may be associated with the progression of colorectal cancer. KeywordsTunicamycin–Swainsonine–Colorectal cancer–Adherens junctions–E-cadherin– N-glycosylation
  Cancer Chemotherapy and Pharmacology 04/2012; 68(1):227-238.
• Article: Irinotecan and oxaliplatin combination as the first-line treatment for patients with advanced non-small cell lung cancer

  Myung Hee Chang, Kyoung Ha Kim, Hyun Jung Jun, Hyo Song Kim, Seong Yoon Yi, Ji Eun Uhm, Min Jae Park, Do Hyoung Lim, Sang Hoon Ji, In Gyu Hwang, Jeeyun Lee, Yeon Hee Park, Jin Seok Ahn, Myung-ju Ahn, Keunchil Park
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  ABSTRACT: BackgroundWe conducted a prospective phase II trial of IrOx in patients with advanced non-small cell lung cancer to evaluate the efficacy and toxicity. Patients and methodsPatients with histologically or cytologically proven non-small cell lung cancer (NSCLC), aged ≥18 years, Eastern Cooperative Oncology Group performance status 0–1, at stage IIIB (pleural effusion)/IV or with recurrent disease not suitable for primary surgical treatment, with no palliative chemotherapy or radiotherapy to the chest or immunotherapy or biologic therapy, the presence of measurable disease by RECIST, and who had given signed written informed consent, were eligible. Treatment consisted of irinotecan 65 mg/m2 on days 1 and 8 and oxaliplatin 130 mg/m2 on day 1, repeated every 3 weeks. ResultsA total of 18 patients were enrolled in June and August 2007, the median age was 59 years (47–73). In total, 71 cycles were administered with a median of 4 cycles per patient (range, 1–6 cycles) and 18 patients were evaluable for treatment response. An independent review of tumor responses gave an overall response rate of 27.7% (CR: 0, PR: 5/18; 95% CI, 7–48.4%) by intent-to-treat analysis. The median overall survival of all patients was 14 months and the median time-to-progression was 4.2 months (95% CI, 1.959–6.441). The most common grade 3/4 toxicities were diarrhea (7% of all cycles) and neutropenia (5.6% of all cycles). Grade 3 peripheral neuropathy occurred in one patient and one patient died due to sepsis. ConclusionThis study suggests that IrOx combination therapy has moderate activity with a tolerable toxicity profile. However, it was not warranted to evaluate further this regimen as first-line treatment for patients with advanced or metastatic NSCLC using the current dosages and schedule.
  Cancer Chemotherapy and Pharmacology 04/2012; 64(5):917-924.
• Article: Phase I study of 3-weekly docetaxel, capecitabine and oxaliplatin combination chemotherapy in patients with previously untreated advanced gastric cancer

  Sun Jin Sym, Min-Hee Ryu, Hye Jin Kang, Sung Sook Lee, Heung-Moon Chang, Jae Lyun Lee, Tae Won Kim, Jeong Hwan Yook, Sung Tae Oh, Byung Sik Kim, Yoon-Koo Kang
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  ABSTRACT: PurposeAdding docetaxel to cisplatin and 5-fluorouracil (5-FU) (DCF) significantly improved clinical efficacy in advanced gastric cancer (AGC). To further improve the efficacy and tolerability, we substituted oxaliplatin for cisplatin and capecitabine for 5-FU in the DCF regimen and performed a phase I study to determine the recommended dose (RD) and dose-limiting toxicity (DLT) of docetaxel, capecitabine and oxaliplatin (DXO) combination in patients with AGC. Materials and methodsPreviously untreated patients with histologically proven metastatic AGC and ECOG performance status 0–2 were enrolled. Docetaxel and oxaliplatin were administered i.v. on day 1. Capecitabine was administered orally bid on days 1–14. Each cycle was repeated every 3weeks. DLTs were evaluated during the first two cycles of treatment. ResultsTwenty-one patients were enrolled: 15 patients in dose-escalation phase and 6 patients in the extension at the RD. Median age was 50years (range 21–65years). At dose level 3 (60mg/m2 docetaxel, 1,000mg/m2 capecitabine, 100mg/m2 oxaliplatin), 1 diarrhea (DLT) was found among 6 patients while at dose level 4 (60mg/m2 docetaxel, 800mg/m2 capecitabine, 130mg/m2 oxaliplatin), 2 DLTs (febrile neutropenia and diarrhea) were observed among 3 patients. Therefore, the dose level 3 was determined as RD. DLTs include grade 3 diarrhea and febrile neutropenia. Cumulative (all cycles) grade 3/4 toxicity included neutropenia (75%), leucopenia (50%), febrile neutropenia (25%), diarrhea (17%), and neuropathy (17%). Of 14 patients with measurable lesions, 11 achieved partial response and 3 showed stable disease. ConclusionThe RD of the DXO regimen in patients with AGC is capecitabine 1,000mg/m2 twice daily on days 1–14, in combination with decetaxel 60mg/m2 (day 1) and oxaliplatin 100mg/m2 (day 1) repeated every 3weeks. The DXO regimen seems to have promising activity and offers an easy alternative to DCF. The toxicities appear to be still substantial, but manageable. KeywordsOxaliplatin-Docetaxel-Capecitabine-Chemotherapy-Gastric cancer
  Cancer Chemotherapy and Pharmacology 04/2012; 66(2):373-380.
• Article: Fixed-dose rate infusion of gemcitabine and weekly cisplatin in elderly or poor performance status patients with unresectable non-small cell lung cancer

  Gyeong-Won Lee, Myung-Hee Kang, Hoon-Gu Kim, Jung Hun Kang, Seok Hyun Kim, Yu Ji Cho, Yi Yeong Jeong, Ho-Cheol Kim, Jong Duk Lee, Young Sil Hwang, Hye Jung Kim, Jong-Seok Lee
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  ABSTRACT: PurposeWe investigated the efficacy and toxicity of a 4-week schedule of a fixed dose rate infusion of gemcitabine and weekly cisplatin in elderly or poor performance status patients with unresectable non-small cell lung cancer (NSCLC). MethodsIn this study, 48 patients with previously untreated NSCLC were given combination chemotherapy that consisted of gemcitabine 1,000mg/m2 (10mg/m2/min fixed dose rate infusion) and cisplatin 25mg/m2, and both drugs were given weekly on days1, 8 and 15. ResultsA partial response and stable disease were observed in 20 patients (41.7%, 95% CI; 27.8–55.6%) and 12 patients (25.0%), respectively. The overall median survival was 10.30months (range: 7.85–12.74months). Major toxicities included neutropenia (grade3 to 4, 29.2%) and infection (grade3 to 4, 27.1%). ConclusionsOur results indicate that this regimen is a feasible treatment for elderly or poor performance status patients with unresectable NSCLC. Nevertheless, the morbidity due to myelosuppression and infection following this treatment should be carefully considered.
  Cancer Chemotherapy and Pharmacology 04/2012; 64(2):385-390.