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Purpose: Fluoropyrimidines are anticancer drugs and can cause hyperammonemia both intravenously and orally. Renal dysfunction may interact with fluoropyrimidine to cause hyperammonemia. We performed quantitative analyses of hyperammonemia using a spontaneous report database to examine the frequency of intravenously and orally administered fluoropyrimidine, the reported frequency of fluoropyrimidine-related regimens, and fluoropyrimidine's interactions with chronic kidney disease (CKD). Methods: This study used data collected between April 2004 and March 2020 from the Japanese Adverse Drug Event Report database. The reporting odds ratio (ROR) of hyperammonemia was calculated for each fluoropyrimidine drug and was adjusted for age and sex. Heatmaps depicting the use of anticancer agents in patients with hyperammonemia were drawn. The interactions between CKD and the fluoropyrimidines were also calculated. These analyses were performed using multiple logistic regression. Results: Hyperammonemia was observed in 861 of the 641,736 adverse events reports. Fluorouracil was the most frequent drug associated with hyperammonemia (389 cases). The ROR of hyperammonemia was 32.5 (95% CI 28.3–37.2) for intravenously administered fluorouracil, 4.7 (95% CI 3.3–6.6) for orally administered capecitabine, 1.9 (95% CI 0.87–4.3) for tegafur/uracil, and 2.2 (95% CI 1.5–3.2) for orally administered tegafur/gimeracil/oteracil. Calcium levofolinate, oxaliplatin, bevacizumab, and irinotecan were the most frequently reported agents in cases of hyperammonemia with intravenously administered fluorouracil. The coefficient of the interaction term between CKD and fluoropyrimidines was 1.12 (95% CI 1.09–1.16). Conclusion: Hyperammonemia cases were more likely to be reported with intravenous fluorouracil than orally administered fluoropyrimidines. Fluoropyrimidines might interact with CKD in hyperammonemia cases. [ABSTRACT FROM AUTHOR]

Purpose: Standard dosages of fluoropyrimidine chemotherapy result in severe toxicity in a substantial proportion of patients, however, routine pre-therapeutic toxicity prediction remains uncommon. A thymine (THY) challenge test can discriminate risk of severe gastrointestinal toxicity in patients receiving fluoropyrimidine monotherapy. We aimed to measure endogenous plasma uracil (U) and its ratio to dihydrouracil (DHU), and assess the performance of these parameters compared with the THY challenge test to evaluate risk of severe toxicity.Methods: Plasma samples, previously collected from 37 patients receiving 5-fluorouracil (5-FU) or capecitabine monotherapy for a THY challenge test (ACTRN12615000586516; retrospectively registered), were assessed for endogenous plasma concentrations of U and DHU using a validated LC-MS/MS method. Renal function was estimated from blood creatinine, and patients with ≥ grade 3 toxicity (CTCAE v4.0) were classified as cases.Results: There were no differences in median endogenous U plasma concentrations or U/DHU ratios between severe toxicity cases and non-cases. Significant differences between cases and non-cases were noted when these measures were normalised to the estimated renal function (CrCL), Unorm p = 0.0004; U/DHUnorm p = 0.0083. These two parameters had a sensitivity of 29%, compared with 57% for the THY challenge test in the same patients. Genotyping for clinically relevant DPYD variants was inferior to either of these pyrimidine phenotyping tests (sensitivity of 14%).Conclusions: The endogenous uracil-based parameters, adjusted to CrCL, were more predictive of increased risk of severe fluoropyrimidine toxicity than DPYD genotyping. However, endogenous U measurement detected fewer cases of severe toxicity than the THY challenge test. [ABSTRACT FROM AUTHOR]

This review considers the "promise" of exploiting the proton-coupled folate transporter (PCFT) for selective therapeutic targeting of cancer. PCFT was discovered in 2006 and was identified as the principal folate transporter involved in the intestinal absorption of dietary folates. The recognition that PCFT was highly expressed in many tumors stimulated substantial interest in using PCFT for cytotoxic drug targeting, taking advantage of its high level transport activity under the acidic pH conditions that characterize many tumors. For pemetrexed, among the best PCFT substrates, transport by PCFT establishes its importance as a clinically important transporter in malignant pleural mesothelioma and non-small cell lung cancer. In recent years, the notion of PCFT-targeting has been extended to a new generation of tumor-targeted 6-substituted pyrrolo[2,3-d]pyrimidine compounds that are structurally and functionally distinct from pemetrexed, and that exhibit near exclusive transport by PCFT and potent inhibition of de novo purine nucleotide biosynthesis. Based on compelling preclinical evidence in a wide range of human tumor models, it is now time to advance the most optimized PCFT-targeted agents with the best balance of PCFT transport specificity and potent antitumor efficacy to the clinic to validate this novel paradigm of highly selective tumor targeting. [ABSTRACT FROM AUTHOR]

Purpose: The impact of proton pump inhibitors (PPIs) on the pharmacokinetics (PK) and efficacy of ceritinib was evaluated.Methods: A healthy subject drug-drug interaction (DDI) study was conducted to assess the effect of esomeprazole on the PK of a single 750 mg dose of ceritinib. To further investigate the impact of PPIs on the PK and efficacy of ceritinib in ALK-positive cancer patients, two subgroup analyses were performed. Analysis 1 evaluated ceritinib steady-state trough concentration (Ctrough,ss) and overall response rate (ORR) by concomitant use of PPIs in patients from the ASCEND-1, -2, and -3 studies; analysis 2 evaluated ceritinib single-dose and steady-state AUC0-24h and C max by concomitant PPI use in patients from ASCEND-1 using a definition of PPI usage similar to that used in the healthy subject study.Results: In the healthy subject study, co-administration of a single 750 mg dose of ceritinib with esomeprazole 40 mg for 6 days decreased ceritinib AUC0-∞ by 76% and C max by 79%. However, based on subgroup analysis 1, patients had similar C trough,ss and ORR regardless of concomitant PPI usage. Based on analysis 2, co-administration of a single 750 mg ceritinib dose with PPIs for 6 days in patients suggested less effect on ceritinib exposure than that observed in healthy subjects as AUC0-24h decreased by 30% and C max decreased by 25%. No clinically meaningful effect on steady-state exposure was observed after daily dosing.Conclusions: Long-term administration of ceritinib with PPIs does not adversely affect the PK and efficacy of ceritinib in ALK-positive cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: Proteasome-inhibiting drugs (PI) are gaining importance in hematologic oncology. The proteasome carries three proteolytically active subunits (β1, β2, β5). All established PI (bortezomib and carfilzomib), as well as experimental drugs in the field (dalanzomib, oprozomib, and ixazomib), by design target the rate-limiting β5 subunit. It is unknown whether β2-selective proteasome inhibition can also be exploited toward anticancer treatment. Combining PI with the pan B-cell-directed Bruton tyrosine kinase inhibitor ibrutinib appears a natural option for future improved treatment of multiple myeloma (MM) and B-cell lymphomas. However, bortezomib induces phosphorylation of IκB and activation of NF-κB in MM cells, while ibrutinib inhibits the IκB/NF-κB axis, suggesting antagonistic signaling. A β2-selective proteasome inhibitor may lack such antagonistic signaling effects. Methods: We recently introduced LU-102, the first β2-selective PI available for preclinical testing. We here compare bortezomib with carfilzomib and LU-102 in MM and MCL in vitro with regard to their effects on pIκB/NF-κB signaling and their cytotoxic activity in combination with ibrutinib. Results: LU-102 reduced phosphorylation of IκB, in contrast to bortezomib and carfilzomib, and was a superior inhibitor of NF-κB activation in MM cells. This translated into highly synergistic cytotoxicity between LU-102 and ibrutinib, which was able to overcome BTZ resistance and CFZ resistance. By contrast, BTZ lacked consistent synergistic cytotoxicity with ibrutinib. Conclusion: Ibrutinib is highly synergistic with β2-selective proteasome inhibition against MM and MCL in vitro. Novel β2-selective proteasome inhibitors may be exploited to overcome bortezomib/carfilzomib resistance and boost the activity of BTK inhibitors against B-cell-derived malignancies. [ABSTRACT FROM AUTHOR]

Purpose: Hangeshashinto (TJ-14, a Kampo medicine), which reduces the level of prostaglandin E2 and affects the cyclooxygenase activity, alleviates chemotherapy-induced oral mucositis (COM). We conducted a double-blind, placebo-controlled, randomized comparative trial to investigate whether TJ-14 prevents and controls COM in patients with colorectal cancer. Methods: Ninety-three patients with colorectal cancer who developed moderate-to-severe COM (WHO grade ≧1) during any cycle of chemotherapy using FOLFOX, FOLFIRI, and/or XELOX treatment were randomly assigned to receive either TJ-14 ( n = 46) or placebo ( n = 47). Patients received the administration of placebo or TJ-14 for 2 weeks at the start of the next course of chemotherapy. Patients were assessed three times per week for safety and for COM incidence and its severity using the WHO grading. Results: Ninety eligible patients (TJ-14; 43, placebo; 47) per protocol set analysis were included in the analysis after the key-opening. Although the incidence of grade ≧2 oral mucositis was lower for patients treated with TJ-14 compared to those treated with placebo, there was no significant difference (48.8 vs. 57.4 %; p = 0.41). The median duration of grade ≧2 mucositis was 5.5 versus 10.5 days ( p = 0.018). No difference in other treatment toxicity was observed between the two groups, and patients exhibited high compliance in dosing administration. Conclusion: The present study results did not meet the primary endpoint. However, TJ-14 demonstrated a significant effect in the treatment of grade ≧2 mucositis in patients with colorectal cancer compared to the placebo. [ABSTRACT FROM AUTHOR]

Purpose: Capecitabine and S-1 are orally administered fluorinated pyrimidines with high-level activity against metastatic breast cancer (MBC). This randomized, multicenter, phase II study compared the activities and safeties of the oral fluoropyrimidines, capecitabine and S-1, in breast cancer patients. Methods: Patients with MBC were randomly assigned to receive capecitabine 825 g/m twice daily on days 1-21 every 4 weeks or S-1 40-60 mg twice daily, according to body surface area, on days 1-28 every 6 weeks. The primary endpoint was progression-free survival (PFS). Results: A total of 142 patients were enrolled and randomized to either capecitabine ( N = 73) or S-1 ( N = 69). Median PFS (progression-free survival) was 1.2 years for capecitabine and 1.3 years for S-1, with a hazard ratio (S-1/capecitabine) of 0.85 (95 % confidence interval [CI] 0.52-1.38) ( P = 0.48 by log-rank). The confirmed objective response rates were 24.0 % for capecitabine and 23.1 % for S-1 ( P = 0.938). The most common treatment-related adverse events were grade 1-2 in intensity. Thrombocytopenia (S-1: 9.2 %, capecitabine: 1.4 %; P = 0.040) and nausea (S-1: 26.2 %, capecitabine: 14.1 %; P = 0.079) were more frequent in the S-1 group, while hand-foot syndrome occurred more often in the capecitabine group (S-1: 10.8 %, capecitabine: 25.4 %; P = 0.029). Conclusions: The results of the current study demonstrate that both S-1 and capecitabine are effective and well-tolerated treatments in patients with MBC, while their adverse events were different. They are both convenient, orally administered drugs, making them attractive agents for use in outpatient treatment. [ABSTRACT FROM AUTHOR]

Purpose: There are several reasons why combining an inhibitor of the vascular endothelial and the platelet-derived growth factor receptor with a taxane might induce synergistic antitumor activity. This phase I study aimed to determine the maximal tolerated dose (MTD) of the combination of pazopanib with two different schedules of docetaxel. Methods: In a 3 + 3 + 3 design, patients with advanced solid tumors received escalating doses of oral pazopanib combined with docetaxel given either every 3 weeks (D3w) or weekly at days 1, 8, and 15 every 28 days (D1w). Pharmacokinetic data of docetaxel and pazopanib were obtained through extensive sampling and WinNonlin modeling. Results: Forty-six patients were enrolled to six dose levels. Both schedules of docetaxel could be combined with 400 mg/day pazopanib. The MTD of D3w docetaxel was 50 mg/m, while for D1w MTD, it was 20 mg/m. In the D3w schedule, the administration of pazopanib led to a 33 % lower docetaxel clearance (mean 31.5 vs 21.1 L/h/m; P = 0.019) and >50 % increase in AUC (mean 1,602 vs 2,414 ng*h/mL; P = 0.029) compared with docetaxel single-agent data. Data for the D1w schedule were comparable. Conclusions: Both treatment schedules of docetaxel combined with pazopanib are feasible but at doses for both drugs that are considerably lower than the recommended single-agent doses. This is largely due to a clinically relevant pharmacokinetic interaction with pazopanib, substantially increasing docetaxel exposure. This interaction is most likely due to CYP3A4 and OATP1B1 inhibition. [ABSTRACT FROM AUTHOR]

Purpose: Ibrutinib is an oral Bruton's tyrosine kinase inhibitor, recently approved for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) patients with at least one prior therapy. We developed a population pharmacokinetic (PK) model for ibrutinib in patients. Methods: Ibrutinib PK data (3,477 observations/245 patients) were available from the following clinical studies: (1) A phase I dose-escalation study in recurrent B cell malignancies (dose levels of 1.25-12.5 mg/kg/day and fixed dose of 560 mg/day); (2) a phase II study in MCL (fixed dose level of 560 mg/day); (3) a phase Ib/II dose-finding study in CLL (fixed dose levels of 420 and 840 mg/day). Different compartmental PK models were explored using nonlinear mixed effects modeling. Results: A two-compartment PK model with sequential zero-first-order absorption and first-order elimination was able to characterize the PK of ibrutinib. The compound was rapidly absorbed, had a high oral plasma clearance (approximately 1,000 L/h) and a high apparent volume of distribution at steady state (approximately 10,000 L). PK parameters were not dependent on dose, study, or clinical indication. The fasting state was characterized by a 67 % relative bioavailability compared with the meal conditions used in the trials and administration after a high-fat meal. Body weight and coadministration of antacids marginally increased volume of distribution and duration of absorption, respectively. Conclusions: The proposed population PK model was able to describe the plasma concentration-time profiles of ibrutinib across various trials. The linear model indicated that the compound's PK was dose independent and time independent. [ABSTRACT FROM AUTHOR]

A combination of monoclonal antibody that binds and inhibits effects induced by vascular endothelial growth factor and tyrosine kinase inhibitor of vascular endothelial growth factor receptor represents a promising concept to block pathological angiogenesis completely. A phase I study combining daily oral pazopanib and bevacizumab (given iv every 2 weeks) was performed in order to determine the maximum tolerated dose of the two drugs in combination. Pazopanib pharmacokinetics were evaluated to compare pharmacokinetic parameters given alone and those observed on the day of the bevacizumab administration. Plasma pazopanib concentrations were obtained in 25 patients treated at two dose levels (400 or 600 mg) at Day 1 (given alone) and Day 15 (the day of the 7.5 mg/kg bevacizumab infusion), and analyzed using the NONMEM program. The apparent oral clearance (CL/ F, mean value of 0.60 L/h) presented an inter-individual variability of 40 %, and an inter-occasion of 27 %. A modest but statistically significant decrease in CL/ F was observed from Day 1 to Day 15 (−16.4, 95 % confidence interval of −8.5 to −27.2 %). However, trough pazopanib concentrations observed at Day 16 (24 h after the bevacizumab iv infusion) were not significantly higher than those observed just before the beginning of the bevacizumab iv infusion, suggesting that the pharmacokinetic change between Day 1 and Day 15 was not due to an interaction of bevacizumab. Overall, the mean observed concentrations at the maximum tolerated pazopanib dose (600 mg) at both Day 1 and Day 15 were higher than those observed at 800 mg once daily level (corresponding to the recommended dose when given alone) during the first-in-man phase 1 study of pazopanib in monochemotherapy. This first population pharmacokinetic analysis of pazopanib shows that inter-individual and inter-study pharmacokinetic variability emphasize the need for further evaluation of therapeutic drug monitoring for pazopanib as suggested for other tyrosine kinase inhibitors. [ABSTRACT FROM AUTHOR]

Purpose: Alisertib (MLN8237) is an investigational inhibitor of Aurora A kinase (AAK). Aurora A plays an essential role in the regulation of spindle assembly and chromosome alignment during mitosis. Inhibition of Aurora A by alisertib in tissue culture has previously been demonstrated to lead to improper chromosomal alignment and disruption of spindle organization, resulting in a transient mitotic delay. The spindle organization defects induced by alisertib have been used to develop a pharmacodynamic (PD) assay for Aurora A inhibition based on the percentage of mitotic cells with proper chromosomal alignment at the metaphase plate (% aligned spindles, abbreviated as AS). The transient mitotic delay that occurs with AAK inhibition permits the use of the mitotic index (the fraction of cells in the population currently undergoing mitosis, abbreviated as MI) as an additional PD assay. When the two PD assays were used in Phase I clinical trials, the reduction in AS was strongly correlated with dose levels and exposures in patients from single time point PD measurements; however, MI failed to show any correlation. To further understand this clinical finding, we constructed PK/PD/efficacy models for AS and MI that can precisely capture the temporal dynamics of the PD markers from in vivo xenograft studies. Methods: A PK/PD study was conducted using a single oral dose of alisertib at 3, 10, and 20 mg/kg in HCT-116 xenografts implanted subcutaneously in mice. An extravascular, two-compartmental pharmacokinetic (PK) model was used to describe the drug kinetics. Consistent with the mechanistic hypothesis for AAK inhibition, the PD biomarkers such as AS and MI were fitted to PK using a direct response inhibitory sigmoid model and an indirect response turnover model, respectively. The antitumor activity of alisertib dosed orally for 21 days with different dose levels and schedules was evaluated. Results: The PK/PD models showed a fast, sustained response for AS after alisertib administration, whereas MI exhibited a slow, transient response. The PK/efficacy relationship for alisertib in HCT-116 xenografts closely corresponds to the PK/PD relationship for the PD markers, with all three IC 50s in close agreement (303, 270, and 280 nM, respectively). Conclusion: The PK/PD and PK/efficacy models show that both AS and MI are equally relevant as mechanism-based PD markers to capture drug activity. However, of the two PD markers, the fast, sustained response of AS makes it the only clinically viable PD marker for defining a dose–response relationship, as its maximal effect can be captured from a wider time window with a single PD sampling; while the window to capture dose-related MI response is narrower. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated the effects of either famotidine or antacid on the pharmacokinetics of nilotinib in healthy subjects, with the specific focus to explore different dosing separation schemes leading to a minimized drug-drug interaction. Methods: Fifty-two subjects were randomized to receive the following treatments in a crossover manner: (A) single oral nilotinib 400 mg alone; (B) famotidine 20 mg twice a day for 3 days, followed by a single administration of nilotinib 400 mg and famotidine 20 mg on Day 4, where famotidine was given 2 h after nilotinib; (C) single oral nilotinib 400 mg and antacid suspension 20 mL, where antacid was given 2 h before nilotinib; (D) single oral nilotinib 400 mg and antacid suspension 20 mL, where antacid was given 2 h after nilotinib. Results: Comparing Treatment B to Treatment A, the geometric mean ratios of nilotinib C, AUC, and AUC were 0.966, 0.984, and 0.911, respectively (90 % confidence intervals (CIs), 0.875-1.066, 0.905-1.069, and 0.798-1.039, respectively). Nilotinib pharmacokinetic parameters following Treatment C or Treatment D were similar to those after Treatment A; the corresponding 90 % CIs of the geometric mean ratios of C, AUC and AUC all fell within the bioequivalence range of 0.8-1.25. Conclusions: Neither famotidine nor antacid significantly affected nilotinib pharmacokinetics. When concurrent use of an H2 blocker or an antacid is necessary, the H2 blocker may be administered 10 h before and 2 h after nilotinib dose, or the antacid may be administered 2 h before or 2 h after nilotinib dose. [ABSTRACT FROM AUTHOR]

Purpose: Capecitabine plus oxaliplatin (XELOX) is an effective second-line regimen for advanced colorectal carcinoma (CRC) patients pretreated with irinotecan. Previous studies have shown supra-additive anti-tumor activity of gemcitabine (GEM) when administered with oxaliplatin. We investigated the dose, toxicity, and efficacy of a second-line XELOXGEM regimen in CRC patients pretreated with irinotecan. Methods: Patients with metastatic or recurrent CRC who failed after a first-line irinotecan-containing regimen received escalating doses of gemcitabine (600, 800, 1,000 mg/m d1, d8) followed by capecitabine (1,000 mg/m b.i.d d1-14) and oxaliplatin (100 mg/m d1) on a 21-day cycle. Results: A total of 38 patients were treated. At 800 mg/m, two of six patients experienced dose-limiting toxicities (diarrhea and thrombocytopenia). Therefore, the clinically recommended dose was defined as 600 mg/m gemcitabine (d1, d8) followed by 1,000 mg/m capecitabine (b.i.d dl-14) and 100 mg/m oxaliplatin (d1). The most common grade 3/4 toxicities were neutropenia (32%), thrombocytopenia (13%), anemia (11%), and peripheral neuropathy (11%). Ten (26.3%) and 23 (60.5%) patients experienced partial response and stable disease, respectively. The median progression-free survival and overall survival were 5.4 months (95% CI 3.8-6.9 months) and 17.7 months (95% CI 8.4-26.9 months), respectively. Conclusions: The XELOXGEM triplet combination is an active and safe second-line regimen for advanced CRC patients pretreated with irinotecan. [ABSTRACT FROM AUTHOR]

Background: This study quantified the impact of drug pathway-associated genetic variants on the pharmacokinetics (PK) of gemcitabine and cisplatin in patients with advanced non-small-cell lung cancer (NSCLC). Methods: Thirty-seven patients with advanced NSCLC were sampled for plasma concentrations of gemcitabine, difluoro-deoxy uridine (dFdU), intracellular gemcitabine triphosphates (dFdCTP), and unbound platinum concentrations after gemcitabine 1,250 mg/m i.v. followed by cisplatin 75 mg/m. We analyzed 13 germline single nucleotide polymorphisms and one deletion-glutathione S-transferase (GST) M1-within six drug pathway-associated genes (GSTM1, GSTP1, cytidine deaminase (CDA), solute carrier (SLC) 28A1, SLC28A2, and deoxycytidine kinase). PK models were fitted to the data using nonlinear mixed-effects modeling, and genetic data were tested on drug PK and hematological toxicity. Results: Patients carrying the nonsynonymous CDA SNP 79A >C (CDA*2) had a 21% lower gemcitabine clearance as compared to wild-type patients (outcomes and complications.0.0009), but the risk for chemotherapy-associated neutropenia (61% vs. 32%, P = 0.07) and severe neutropenia (17% vs. 5%, P = 0.26) was not significantly higher. Other gene polymorphisms were not associated with drug PK parameters or hematological toxicity. The known functional mutant variant CDA*3 was not found in any of the patients. Conclusions: Although the mutant CDA*2 allele results in an increased exposure to gemcitabine in Caucasian patients, this study gives no definite conclusion on the clinical relevance of this finding. Further studies should look into the relationship between CDA genotypes, plasmatic CDA activity, and clinical outcome in patients receiving gemcitabine-based chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: PEFG regimen (P:cisplatin, E:epirubicin, F:5-fluorouracil, G:gemcitabine) significantly prolonged progression-free (PFS) and overall survival (OS) of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. The current trial was aimed at assessing whether the replacement of E with docetaxel (D) may improve 6 months PFS (PFS6). Methods: Chemo-naive patients with stage III or metastatic PA received P (30 mg/m day 1 and 15), G (800 mg/m day 1 and 15), and capecitabine (1,250 mg/m/day days 1-28, without a break) and were randomized to receive either D at 25-30 mg/m day 1 and 15 (arm A: PDXG regimen) or E at 30 mg/m day 1 and 15 (arm B: PEXG regimen). Cycles were repeated every 28 days for a maximum of 6 months. The Fleming design was used to calculate the sample size on the probability of being PFS6. Assuming P0 = 40% and P1 = 60%, α = 0.05 and β = 0.10; the study was to enroll 52 patients per arm. Results: Between July 2005 and September 2008, 105 patients were enrolled, stratified by stage and randomized. Patients' characteristics were (A/B) the following: median age 61/59, PS >70 92/88%, metastatic disease 66/65%. PFS6 was 58%, and median OS was 11 months in both arms. A partial response was observed in 60/37% of patients. Main per cycle G3-4 toxicity was the following: neutropenia 4/13%, thrombocytopenia 2/4%, anemia 4/4%, and fatigue 6/3%. Conclusions: The inclusion of D instead of E yielded more objective response and less G3-4 neutropenia but did not improve PFS and OS. The present trial confirms the relevant impact on outcome of advanced PA of 4-drug regimens. [ABSTRACT FROM AUTHOR]

Purpose: Antiangiogenic drugs inhibit tumor growth by decreasing blood supply and causing transient 'normalization' of the tumor vasculature, thereby improving the delivery of systemic chemotherapy. A higher dose of antiangiogenic drugs may lead to a more marked decrease in intratumoral blood flow but may concomitantly cause a decrease in delivery of chemotherapeutic agents. The purpose of this study was to define an optimal schedule for the combination of gemcitabine with a recombinant endostatin, endostar. Methods: We evaluated the antitumor effects with different schedules of gemcitabine combined with or without endostar. The changes of vascular endothelial growth factor (VEGF) levels in tumor extracts and sera after gemcitabine treatment were examined. Endostar was also assessed for its abilities to inhibit the increase in VEGF levels. Apoptotic cells and microvessel density within tumor tissue were also examined. Results: Endostar administered simultaneously with or following gemcitabine improved the inhibition of tumor growth, compared with gemcitabine alone. VEGF levels decreased immediately after gemcitabine treatment, but increased in the following several days. Endostar administered simultaneously with or following gemcitabine could inhibit the increase in VEGF levels, thereby cause a decreased vessel density and an increased apoptosis in tumor tissue. Conclusions: Our finding suggested that endostar given simultaneously with or following gemcitabine might be optimal to enhance the antitumor effect. [ABSTRACT FROM AUTHOR]

Purpose: Eniluracil (EU) is a potent dihydropyrimidine (DPD) inhibitor, which improves the oral bio-availability of 5-fluorouracil (5-FU) and may overcome fluoropyrimidine (FP) resistance in hepatocellular carcinoma (HCC). Based on preclinical evidence, we aimed at studying a new dosing schedule for the combination with sequential administration, a lower dose of EU and higher doses of 5-FU than previously investigated. Methods: Patients with a diagnosis of hepatocellular carcinoma were eligible for this Phase 1/2 study. The primary endpoint for the Phase 1 was the determination of dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of oral 5-FU when given 14 h after oral EU 5 mg, weekly for 3 out of 4 weeks. The starting dose of 5-FU was 20 mg, followed by 30 mg and 80 mg. Secondary endpoints were anti-tumor activity, pharmacokinetics, and DPD activity in peripheral blood mononuclear cells. RECIST was used for assessment of efficacy and NCI CTC-AE version 3.0 for describing toxicity. Results: Nine patients enrolled in the trial. Median age was 53 years. All patients were Asian (one from Hawaii, 8 from Singapore). Prior treatment was as follows: liver surgery, 2 patients; chemo-embolization, 2 patients; thalidomide, 3 patients; adriamycin, 3 patients. Patients received a median of 2 cycles (range, 1-14) of therapy. No DLTs were seen up to the 80-mg 5-FU cohort. Out of 3 patients in the 80-mg cohort, one had pancytopenia. One patient at the 20-mg cohort had stable disease that lasted for 14 months. Conclusion: EU, at a 5.0-mg weekly dose, was well tolerated. There was no evidence of dose-related safety effects. This trial did not define the MTD for oral 5-FU. No objective responses by RECIST were noted but one patient had stable disease and a decrease of 28% in the sum of the largest diameters of her target lesions. The study was terminated early because of CNS-related toxicities noted in the single higher dose levels in a companion study, AHX-03-104. [ABSTRACT FROM AUTHOR]

Purpose: 5-Fluorouracil (5-FU), acting as a pyrimidine antagonist, is a major chemotherapy drug used for the treatment of tumors such as gastrointestinal, breast, ovary, and head and neck cancers. The key and rate-limiting enzyme in 5-FU catabolism is dihydropyrimidine dehydrogenase (DHPDH), whose partial or complete deficiency exposes to a severe 5-FU toxicity in patients. The determination of DHPDH activity in patients before the treatment and setting up a personalized therapy for each patient receiving the drug can help us to prevent the possible risk of toxicity. Methods: To isolate peripheral blood mononuclear cells (PBMCs), EDTA-anticoagulated blood samples were collected from randomly selected 47 patients and examined for 5-FU and its metabolite dihydrofluorouracil (FUH2) by using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) to observe DHPDH activity at different intervals (0 and 4th hour) indirectly. Results: Intra-assay and interassay CV % values of samples from the measurements of the modified methods are found 1.3-11.9, 2.3-9.4 for 5-FU and 3.1-14.4, 3.3-12.6 for FUH2, respectively. The reference values derived from 45 patients treated with 5-FU are 1.84 ± 0.34 ug/gr protein for 5-FU, 40.15 ± 11.43 ng/gr protein for FUH2, respectively. FUH2/5-FU ratio is 21.9 ± 3.72. In addition, the results determined from two patients, in which the lack of DHPDH is considered, were 3.24 and 4.16 ug/gr protein for 5-FU, 4.1 and 6.7 ng/gr protein for FUH2. FUH2/5-FU ratio is 1.26 and 1.61. Conclusion: The measurements of 5-FU, FUH2, and especially their ratio (FUH2/5-FU) by the modified LC-MS/MS method could be used to determine DHPDH enzyme activity. [ABSTRACT FROM AUTHOR]

It has been suggested that the gene expression levels of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) help in the prediction of the response to 5-fluorouracil (5-FU) in vivo and in vitro in gastric cancers. In this study, intratumoral TS and DPD gene expressions were evaluated with real time reverse transcriptional polymerase chain reaction technique to determine the correlation between the expression of these two genes and in vitro sensitivity to 5-FU, assessed by the histoculture drug response assay on 87 patients with gastric adenocarcinoma. The sensitivity to 5-FU did not show any difference in clinicopathological groups. DPD gene level was higher in undifferentiated ( n = 39) than differentiated ( n = 48) tumors ( P = 0.043). In differentiated tumors, TS gene expression levels were higher in the tumors with relative resistance to 5-FU, while in undifferentiated cases, DPD mRNA levels were higher in tumors that showed resistance to 5-FU in vitro ( P = 0.043 and 0.007, respectively). DPD also had significant predictive value for 5-FU sensitivity in undifferentiated cases [ R(S) = −0.401, P = 0.011]. TS and DPD gene expression levels were more highly correlated in undifferentiated compared to differentiated cases [ R(S) = 0.515 and 0.359, respectively]. Different gene expression might be responsible for 5-FU sensitivity in gastric cancers of different histologic origin. [ABSTRACT FROM AUTHOR]

Background: Hemolytic anemia has been noted during treatment with a variety of chemotherapeutic agents. We observed mild compensated hemolytic anemia in a patient receiving capecitabine during a randomized, controlled trial of adjuvant therapy. In order to investigate the hypothesis that hemolysis is the underlying cause of the hyperbilirubinemia sometimes observed during capecitabine treatment, we evaluated factors associated with hemolysis in ten patients. Factors were also analyzed in ten patients receiving 5-fluorourocil/leucovorin (5-FU/LV). Methods: Twenty chemotherapy-naïve patients undergoing surgery for Dukes’ C colon cancer were included in the phase III, ‘X-ACT’ trial, and randomized to receive 24-week adjuvant treatment with either oral capecitabine (eight cycles of 1,250 mg/m2 twice daily for 14 days, followed by a 7-day rest period) ( n=10) or 5-FU/LV administered according to the Mayo Clinic regimen (six cycles of LV 20 mg/m2 followed by 5-FU 425 mg/m2, administered as an i.v. bolus on days 1–5 every 28 days) ( n=10). Ten patients randomized in each treatment arm were evaluated. Hemolytic parameters evaluated included bilirubin, lactate dehydrogenase, haptoglobin, and reticulocytes. Results: Seven patients receiving capecitabine and three patients receiving 5-FU/LV experienced grade 1/2 elevations of bilirubin during the 24-week treatment period. In most cases, hyperbilirubinemia was associated with concomitant alterations in other hemolytic parameters. Five episodes of grade 1 compensated hemolytic anemia were reported in four capecitabine-treated patients, all of which were associated with hyperbilirubinemia. Conclusion: Adjuvant treatment with capecitabine or 5-FU/LV in a small sample of patients with Dukes’ C colon cancer was associated with alterations in hemolytic parameters. These alterations, in particular hyperbilirubinemia, were associated in some patients with low-grade compensated hemolytic anemia. All changes were clinically insignificant, fully reversible, and may represent a fluoropyrimidine class effect. Further studies are indicated to evaluate the incidence and implications of this effect. [ABSTRACT FROM AUTHOR]

Purpose: Experimental studies have shown that mitomycin C (MMC) acts synergistically with irinotecan. We evaluated the antitumor activity and toxicity of a combination of irinotecan and MMC in patients with metastatic colorectal cancer resistant to fluoropyrimidines.Methods: Eligible patients had evidence of tumor progression while receiving fluoropyrimidine-based regimens or had disease recurrence within 6 months after the completion of adjuvant treatment with fluoropyrimidines. Irinotecan (150 mg/m(2)) and MMC (5 mg/m(2)) were administered on days 1 and 15 of a 28-day cycle. Treatment was repeated every 4 weeks.Results: Among the 41 patients enrolled, 37 (90%) had received previous chemotherapy for metastatic disease, and 4 had received adjuvant chemotherapy alone. Objective responses were observed in 14 patients (34%, 95% confidence interval 20-49%). The median time to progression was 4.2 months, and the median survival time was 11.9 months. The study treatment was well tolerated; the median number of cycles received was four. Grade 3 or 4 neutropenia, the most common toxic effect, occurred in 20 patients (49%). Grade 3 or 4 thrombocytopenia occurred in four patients (10%) and grade 3 diarrhea in one patient.Conclusions: Our results suggest that irinotecan and MMC combination therapy is effective and well tolerated in patients with fluoropyrimidine-resistant metastatic colorectal cancer. Further clinical investigation of this regimen is warranted. [ABSTRACT FROM AUTHOR]

The anti-HER-2 antibody, trastuzumab (Herceptin), and the oral fluoropyrimidine, capecitabine (Xeloda), are both effective in breast cancer with different modes of action and toxicity profiles. Therefore, the efficacy in combination therapy of these agents for the treatment of HER-2-overexpressing breast cancer was of interest. An antagonistic interaction in vitro between trastuzumab and 5-fluorouracil (5-FUra) in combination has previously been reported. In the same study, the in vivo antitumor activity of this combination was investigated. However, the results were inconclusive since 5-FUra at the dose used had sufficient antitumor efficacy as a single agent and therefore it was not possible to clarify the potential difference between 5-FUra alone and the combination. In the present study, we investigated the efficacy of trastuzumab in combination with capecitabine or its intermediate metabolite 5′-dFUrd in HER-2-overexpressing human breast cancer cell lines and xenograft models. In vivo antitumor activity of the combination was at least additive, in terms of tumor growth inhibition and tumor growth delay, in human breast cancer models KPL-4 and BT-474. The combination treatment in vivo was superior to the treatment with either single agent alone, even though in vitro treatment with trastuzumab and 5′-dFUrd/5-FUra showed antagonistic antiproliferative activity in these cell lines. The reason for the discrepancy between the in vivo and in vitro results was not clarified. However, observed additive in vivo antitumor activity clearly indicates that the clinical efficacy of the combination of trastuzumab and capecitabine/5′-dFUrd against HER-2-overexpressing breast cancer is worth investigating. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this investigation was to evaluate the effectiveness of oral 5-(phenylthio)acyclouridine (PTAU) in improving the oral bioavailability of uridine. PTAU is a new potent and specific inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in uridine catabolism. PTAU is not toxic to mice and is fully absorbed after oral administration (100% oral bioavailability). Methods: PTAU was administered orally to mice alone or with uridine. The plasma levels of PTAU as well as those of uridine and its catabolite uracil were measured using HPLC, and pharmacokinetic analysis was performed. Results: Coadministration of PTAU with uridine elevated the concentration of plasma uridine in a dose-dependent manner over that resulting from the administration of the same dose of uridine alone, and reduced the clearance of uridine as well as the peak plasma concentration (Cmax) and area under the curve (AUC) of plasma uracil. Coadministration of PTAU at 30, 45 and 60 mg/kg improved the low oral bioavailability (7.7%) of uridine administered at 1320 mg/kg by 4.3-, 5.9- and 9.9-fold, respectively, and reduced the AUC of plasma uracil (1227.8 µmol·h/l) by 5.7-, 6.8- and 8.2-fold, respectively. Similar results were observed when PTAU was coadministered with lower doses of uridine. Oral PTAU at 30, 45 and 60 mg/kg improved the oral bioavailability of 330 mg/kg uridine by 1.8-, 2.6- and 2.8-fold, and that of 660 mg/kg uridine by 2.2-, 2.6- and 3.2-fold, respectively. Conclusion: The effectiveness of PTAU in improving the oral bioavailability of uridine could be useful in the rescue or protection from host toxicities of various chemotherapeutic pyrimidine analogues as well as in the management of medical disorders that are remedied by administration of uridine. [ABSTRACT FROM AUTHOR]

Purpose: Several trials have suggested that intrahepatic chemotherapy increases the likelihood of response in advanced colon cancer patients, but has no significant impact on survival due to the development of extrahepatic metastases. We report our experience of combined hepatic intraarterial and systemic chemotherapy in advanced colorectal cancer patients.Methods: A group of 35 patients received intrahepatic FUDR (0.3 mg/kg per day for 14 days by continuous infusion), followed, after 1 week's rest, by systemic 5-FU and L-leucovorin (370 and 100 mg/m2 per day, respectively, both for 5 consecutive days). After another week off therapy, the combined intrahepatic and systemic regimen was repeated and cycles continued until disease progression.Results: Of 32 assessable patients, 17 (53.1%) had an objective response, while 8 (25%) had disease stabilization. Median time to progression (TTP) was 32 weeks (range 8-104 weeks), while the median overall survival was only 39 weeks (range 9-109 weeks). Incomplete liver perfusion was the only variable that showed a significant correlation with a poorer survival (P = 0.046, log-rank test).Conclusions: Our results are in agreement with previous data suggesting a relative efficacy of such a treatment approach for advanced colon cancer patients. More thorough investigations are warranted, especially as an adjuvant treatment for selected high-risk patients. [ABSTRACT FROM AUTHOR]

Purpose: To assess the pharmacokinetics of Ftorafur (tegafur, FT), 5-fluorouracil (5-FU), and uracil in 31 cancer patients who were enrolled in phase I studies of oral uracil and FT (UFT). The correlation between pharmacokinetic parameters and toxic effects of UFT was evaluated. Methods: Uracil and FT were orally administered in a 4:1 molar ratio at FT doses of 200–400 mg/m2 per day. Patients also received leucovorin at 150 mg/day. Daily doses were divided into three doses and administered at 8-h intervals for 28 consecutive days. Plasma FT concentrations were measured by high-performance liquid chromatography, and plasma 5-FU and uracil concentrations were determined using gas chromatography-mass spectrometry. National Institutes of Health Common Toxicity Criteria were used for assessment of toxicity. Results: The concentrations of FT, 5-FU, and uracil showed wide interpatient variations. Maximum plasma concentrations (Cpmax) of all three compounds were achieved in 0.3 to 4.0 h. At the various study doses, the terminal half-life (t1/2β) of FT ranged from 3.9 to 5.9 h, the area under the concentration-versus-time curve (AUC0–6h) ranged from 16,220 to 52,446 (ng/ml)h, the total clearance (ClT) ranged from 100 to 175 ml/min, and the steady-state volume of distribution (Vdss) ranged from 18.3 to 28.7 l. The 5-FU generated from FT had an apparent distribution half-life (t1/2α) and an apparent elimination half-life (t1/2β) of 0.3–1.3 h and 4.9–7.0 h, respectively. The AUC0–6h of 5-FU ranged from 120 to 325 (ng/ml)h. Uracil had a t1/2α of 0.2–0.5 h and the level quickly returned to the endogenous level. The AUC0–6h for uracil ranged from 605 to 3764 (ng/ml)h, the ClT ranged from 3225 to 7748 ml/min, and the Vdss ranged from 341 to 1354 l. The Cpmax and AUC0–6h of both FT and uracil were significantly correlated with FT doses (P-values of 0.0244 and 0.0112) and with uracil doses (P-values of 0.0346 and 0.0083), respectively. In addition to interpatient variations, intrapatient variations were also observed in six patients who had pharmacology studies done on days 1 and 26 ± 2 at the same study dose. We found that the repeated treatment with UFT caused cumulative increases in the values of Cpmax, Ctrough, and AUC0–6h of FT and 5-FU. The major toxic effects observed were diarrhea and nausea and vomiting. The occurrence of these toxic effects correlated significantly with the Cpmax and AUC0–6h of 5-FU. Conclusions: The pharmacology studies showed that FT and uracil were readily absorbed orally and that FT was rapidly converted to 5-FU. The preliminary findings suggest that determination of plasma levels of 5-FU after oral administration of UFT may help predict subsequent toxic effects. [ABSTRACT FROM AUTHOR]