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1.
Hironori Iwasaki Takafumi Okabe Kensaku Takara Yasuhiko Yoshida Kaoru Hanashiro Hirosuke Oku 《Cancer chemotherapy and pharmacology》2010,65(5):953-959
Purpose
This study examined the pharmacokinetics of irinotecan (CPT-11), active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), SN-38 glucuronide (SN-38G) amrubicin (AMR), and active metabolite amrubicinol (AMR-OH) after intravenous administration of this combination therapy in rats.Methods
Male Sprague-Dawley rats were treated with 10 mg/kg CPT-11 with 10 mg/kg AMR. AMR, AMR-OH, CPT-11, SN-38 and SN-38G were measured in plasma, bile, and tissues using high-performance liquid chromatography.Results
Co-administration of CPT-11 resulted in a significant decrease in plasma concentrations and area under the curves (AUC) of AMR-OH compared with treatment with AMR alone. On the other hand, co-administration of AMR resulted in a slight increase in the initial plasma concentration of SN-38; however, there were no differences in AUC values in CPT-11 and SN-38. The cumulative biliary excretion curves of AMR, CPT-11, and their active metabolites were not changed. CPT-11 inhibited the conversion of AMR to AMR-OH in rat cytosolic fractions.Conclusions
CPT-11 did not affect the pharmacokinetic of AMR but decreased the plasma concentration of AMR-OH and might affect the formation of AMR-OH from AMR in hepatocytes. 相似文献2.
Crystal S. Denlinger Rebecca Blanchard Lu Xu Coen Bernaards Samuel Litwin Cynthia Spittle Daniel J. Berg Susan McLaughlin Maryann Redlinger Andrew Dorr Julie Hambleton Scott Holden Anne Kearns Sara Kenkare-Mitra Bert Lum Neal J. Meropol Peter J. O’Dwyer 《Cancer chemotherapy and pharmacology》2009,65(1):97-105
Purpose
The purpose of this study was to evaluate the effect of bevacizumab on the pharmacokinetics (PK) of irinotecan and its active metabolite. Exploratory analyses of the impact of variability in uridine diphosphate glucuronosyltransferase 1A (UGT1A) genes on irinotecan metabolism and toxicity were conducted.Methods
This was an open-labeled, fixed-sequence study of bevacizumab with FOLFIRI (irinotecan, leucovorin, and infusional 5-fluorouracil). Pharmacokinetic assessments were conducted in cycles 1 and 3.Results
Forty-five subjects were enrolled. No difference in dose-normalized AUC0–last for irinotecan and SN-38 between irinotecan administered alone or in combination with bevacizumab was identified. Leukopenia was associated with higher exposure to both irinotecan and SN-38. UGT1A1 polymorphisms were associated with variability in irinotecan PK. Gastrointestinal toxicity was associated with UGT1A6 genotype. No other associations between UGT1A genotypes and toxicity were detected.Conclusion
Bevacizumab does not affect irinotecan PK when administered concurrently. A variety of pharmacogenetic relationships may influence the pharmacokinetics of irinotecan and its toxicity. 相似文献3.
Kouichi Hirose Koushiro Yamashita Hirofumi Takada Noriko Kaneda Kohei Fukami Eiji Maruo Mizuho Kitamura Junichi Hasegawa Yorinobu Maeda 《International journal of clinical oncology / Japan Society of Clinical Oncology》2014,19(2):397-402
Background
It was recently reported that genetic polymorphisms of UDP glucuronyltransferase-1 polypeptide A1 (UGT1A1), a glucuronidation enzyme, were associated with irinotecan (CPT-11) metabolism. The active metabolite of CPT-11, 7-ethyl-10-hydroxycamptothecin (SN-38) was glucuronidated (SN-38G) by UGT1A1. Genetic polymorphisms of UGT1A1 were associated with potentially serious adverse events, including neutropenia. Several studies have suggested that the dose of CPT-11 should be decreased in patients homozygous for UGT1A1*6 or UGT1A1*28, or double heterozygotes (*6/*28). However, the reference dose for patients with these genetic polymorphisms is unclear.Methods
We investigated the relationship between the SN-38G/SN-38 concentration ratio and the dose of CPT-11 in 70 patients with colorectal cancer who received FOLFIRI-based regimens, by measuring the plasma concentrations of CPT-11, SN-38, and SN-38G.Results
The SN-38G/SN-38 concentration ratio was lower in patients who were homozygous for UGT1A1*6, heterozygous for UGT1A1*6 or UGT1A1*28, or were double heterozygotes compared with patients with wild-type genes. The relative decreases in the SN-38G/SN-38 concentration ratio in patients homozygous for UGT1A1*6 and in double heterozygotes were greater than in patients heterozygous for UGT1A1*6 or UGT1A1*28. Interestingly, decreases in the SN-38G/SN-38 concentration ratio were associated with decreases in the neutrophil count and the final infusion dose of CPT-11.Conclusion
Our results suggest that the SN-38G/SN-38 concentration ratio is an important factor for guiding dose adjustments, even in patients with wild-type genes. Therefore, the SN-38G/SN-38 concentration ratio, as an index of the patient’s metabolic capacity, is useful for assessing dose adjustments of CPT-11. 相似文献4.
Kyu-pyo Kim Ho-Sook Kim Sun Jin Sym Kyun Seop Bae Yong Sang Hong Heung-Moon Chang Jae Lyun Lee Yoon-Koo Kang Jung Shin Lee Jae-Gook Shin Tae Won Kim 《Cancer chemotherapy and pharmacology》2013,71(6):1609-1617
Purpose
UGT1A1 genotypes are important when considering treatment with irinotecan-containing regimens. In this study, we determined the dose, efficacy, and tolerability of irinotecan according to UGT1A1 genotypes when combined with capecitabine in patients with metastatic colorectal cancer.Methods
Patients with histologically confirmed metastatic adenocarcinoma of the colon or rectum were enrolled into a UGT1A1 genotype-directed dose-escalation trial of irinotecan plus fixed-dose capecitabine (2,000 mg/m2/day). The starting dose of irinotecan was different for each genotype group and ranged from 200 to 280 mg/m2. Pharmacokinetic concentrations of irinotecan and metabolites were determined by LC/MS/MS.Results
Fifty patients were genotyped for UGT1A1 *28 and *6, and grouped according to the numbers of defective alleles (DA): 0, 1, and 2. Plasma concentrations of irinotecan, SN-38, and SN-38G were measured. The maximum tolerated dose of irinotecan was 350 mg/m2 for the 0 and 1 DA groups, and 200 mg/m2 for the 2 DA group. For the 0, 1, and 2 DA groups, mean AUClast ratios of SN-38G to SN-38 were 7.72, 5.71, and 2.72 (P = 0.0023) and relative dose intensities at recommended dose were 85, 83, and 97 %.Conclusion
Irinotecan dosing based on UGT1A1*28 and *6 is feasible, and higher doses of irinotecan can be safely administered in patients with 0 or 1 DA, compared to those with 2 DA. 相似文献5.
Yosuke Horita Y. Yamada Y. Hirashima K. Kato T. Nakajima T. Hamaguchi Y. Shimada 《Cancer chemotherapy and pharmacology》2010,65(3):467-471
Purpose
Bevacizumab (BV) prolongs the survival of colorectal cancer patients when combined with irinotecan (CPT-11)-based regimens. In the AVF2107g study, the area under the curve (AUC) ratio for bolus CPT-11/5-fluorouracil (5-FU)/leucovorin (LV) (IFL) with the BV arm to bolus IFL with placebo indicated that SN-38 concentrations may have been increased in subjects receiving BV. However, the mechanism underlying such increase remains unclear, and the difference might be caused by an imbalance between the two arms and a possible inter-subject variability of CPT-11 metabolism. Within-subject comparisons were used to evaluate the effect of BV on advanced colorectal cancer patients when administered with the FOLFIRI regimen as second-line chemotherapy.Methods
Ten advanced colorectal cancer patients received the FOLFIRI regimen every 2 weeks. At cycle 1, BV was administered following FOLFIRI administration to allow baseline pharmacokinetic (PK) analysis of CPT-11 and its metabolites. From cycle 2, BV was administered just before FOLFIRI administration. Plasma samples were collected under the same condition (at cycle 3).Results
There were no significant differences in the C max and AUC0-∞ of CPT-11, SN-38, and SN-38G between cycle 1 (without BV) and cycle 3 (with BV). PK parameters of CPT-11, SN-38, and SN-38G were not significantly affected by BV. There were no significant differences in the changes in the AUC ratio of CPT-11 to SN-38 between cycles 1 and 3, as well as in the ratio of SN-38 to SN-38G.Conclusion
BV does not affect the plasma concentration of CPT-11 and its metabolites on FOLFIRI regimen. 相似文献6.
R. C. Brennan W. Furman S. Mao J. Wu D. C. Turner C. F. Stewart V. Santana L. M. McGregor 《Cancer chemotherapy and pharmacology》2014,74(6):1191-1198
Purpose
This phase I study endeavored to estimate the maximum tolerated dose and describe the dose-limiting toxicities (DLTs) of oral irinotecan with gefitinib in children with refractory solid tumors.Methods
Oral irinotecan was administered on days 1–5 and 8–12 with oral gefitinib (fixed dose, 150 mg/m2/day) on days 1–12 of a 21-day course. The escalation with overdose control method guided irinotecan dose escalation (7 dose levels, range 5–40 mg/m2/day).Results
Sixteen of 19 patients were evaluable, with serial pharmacokinetic studies in ten patients. Diagnoses included osteosarcoma (N = 5), neuroblastoma (N = 3), sarcoma (N = 3), and others (N = 5). Patients received a median of two courses (range 1–20), with at least two patients treated on dose levels 2–7. Three patients had five DLTs; the most common being metabolic (hypokalemia, N = 2 and hypophosphatemia, N = 1) at dose levels two (10 mg/m2) and four (20 mg/m2). One patient experienced grade 3 diarrhea (40 mg/m2). Irinotecan bioavailability was 2.5-fold higher when co-administered with gefitinib, while the conversion rate of irinotecan to SN-38 lactone was unaffected. The study closed due to poor accrual before evaluation of the next recommended irinotecan dose level (35 mg/m2). Of 11 patients receiving at least two courses of therapy, three had stable disease lasting two to four courses and one patient maintained a complete response through 18 courses.Conclusions
The combination of oral gefitinib and irinotecan has acceptable toxicity and anti-tumor activity in pediatric patients with refractory solid tumors. Pharmacokinetic analysis confirms that co-administration of gefitinib increases irinotecan bioavailability leading to an increased SN-38 lactone systemic exposure. 相似文献7.
Bastianina Canu Anna Fioravanti Paola Orlandi Teresa Di Desidero Greta Alì Gabriella Fontanini Antonello Di Paolo Mario Del Tacca Romano Danesi Guido Bocci 《Neoplasia (New York, N.Y.)》2011,13(3):217-229
Aims
To demonstrate the synergistic antiproliferative and proapoptotic activity of irinotecan and axitinib in vitro and the improvement of the in vivo effects on angiogenesis and pancreatic cancer.Methods
Proliferation and apoptotic assays were performed on human dermal microvascular endothelial cells and pancreas cancer (MIAPaCa-2, Capan-1) cell lines exposed to SN-38, the active metabolite of irinotecan, axitinib, or their simultaneous combination for 72 hours. ERK1/2 and Akt phosphorylation, the vascular endothelial growth factor (VEGF), VEGF receptor-2, and thrombospondin-1 (TSP-1) concentration were measured by ELISAs. ATP7A and ABCG2 gene expression was performed with real-time polymerase chain reaction and SN-38 intracellular concentrations were measured by high-performance liquid chromatography. Capan-1 xenografts in nude mice were treated with irinotecan and axitinib alone or in simultaneous combination.Results
A strong synergistic effect on antiproliferative and proapoptotic activity was found with the axitinib/SN-38 combination on endothelial and cancer cells. ERK1/2 and Akt phosphorylation were significantly inhibited by lower concentrations of the combined drugs in all the cell lines. Axitinib and SN-38 combined treatment greatly inhibited the expression of the ATP7A and ABCG2 genes in endothelial and cancer cells, increasing the SN-38 intracellular concentration. Moreover, TSP-1 secretion was increased in cells treated with both drugs, whereas VEGFR-2 levels significantly decreased. In vivo administration of the simultaneous combination determined an almost complete regression of tumors and tumor neovascularization.Conclusions
In vitro results show the highly synergistic properties of simultaneous combination of irinotecan and axitinib on endothelial and pancreas cancer cells, suggesting a possible translation of this schedule into the clinics. 相似文献8.
Toshihiko Doi Kei Muro Takayuki Yoshino Nozomu Fuse Takashi Ura Daisuke Takahari Hwa-ping Feng Takashi Shimamoto Kazuo Noguchi Atsushi Ohtsu 《Cancer chemotherapy and pharmacology》2013,72(3):643-652
Purpose
The safety, tolerability, and pharmacokinetic (PK) interactions of MK-0646 in combination with cetuximab and irinotecan were investigated in Japanese patients with advanced colorectal cancer.Methods
Twenty patients were treated in the following study arms in combination with cetuximab and irinotecan: A [MK-0646 (10 mg/kg) weekly starting on Day 22], B [MK-0646 (15 mg/kg) on Day 8, followed by 7.5 mg/kg every 2 weeks], or C [MK-0646 (10 mg/kg) on Day 1 and weekly starting on Day 22]. Dose limiting toxicities (DLTs) were evaluated during a prespecified 4-week period in arms A and B. Full PK sampling was performed to evaluate the PK interactions.Results
One of the 6 evaluable patients in arm A developed a DLT (grade 3 hyperglycemia); no DLTs occurred in the 6 patients in arm B. Common treatment-related adverse events included leukopenia, neutropenia, dermatitis acneiform, paronychia, nausea, stomatitis, diarrhea, and decreased appetite. The co-administration of cetuximab and irinotecan with MK-0646 increased the MK-0646 AUC0–168h by 25 %, with MK-0646 accumulation from the previous dose contributing to the observed increase. The co-administration of MK-0646 with cetuximab and irinotecan did not affect the PK of cetuximab and irinotecan, but reduced the C max (from 16.8 to 13.0 ng/mL) and the AUC0–24h (by 13 %) of SN-38, the active metabolite of irinotecan.Conclusions
The triple combination of MK-0646, cetuximab, and irinotecan was well tolerated in Japanese patients with advanced colorectal cancer. These results indicate a minimal potential for PK interactions between MK-0646 and cetuximab and between MK-0646 and irinotecan/SN-38. 相似文献9.
A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies 总被引:1,自引:0,他引:1
Paula M. Fracasso Kerry J. Williams Ronald C. Chen Joel Picus Cynthia X. Ma Matthew J. Ellis Benjamin R. Tan Timothy J. Pluard Douglas R. Adkins Michael J. Naughton Janet S. Rader Matthew A. Arquette James W. Fleshman Allison N. Creekmore Sherry A. Goodner Lisa P. Wright Zhanfang Guo Christine E. Ryan Yu Tao Eliane M. Soares Shi-rong Cai Li Lin Janet Dancey Michelle A. Rudek Howard L. McLeod Helen Piwnica-Worms 《Cancer chemotherapy and pharmacology》2011,67(6):1225-1237
Purpose
UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors.Experimental design
Patients received irinotecan (75?C125?mg/m2 IV on days 1, 8, 15, 22) and UCN-01 (50?C90?mg/m2 IV on day 2 and 25?C45?mg/m2 on day 23 and subsequent doses) every 42?days. Blood for pharmacokinetics of UCN-01 and irinotecan, and blood, normal rectal mucosa, and tumor biopsies for pharmacodynamic studies were obtained.Results
Twenty-five patients enrolled to 5 dose levels. The MTD was irinotecan 125?mg/m2 on days 1, 8, 15, 22 and UCN-01 70?mg/m2 on day 2 and 35?mg/m2 on day 23. DLTs included grade 3 diarrhea/dehydration and dyspnea. UCN-01 had a prolonged half-life and a low clearance rate. There was a significant reduction in SN-38 Cmax and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives. Phosphorylated ribosomal protein S6 was reduced in blood, normal rectal mucosa, and tumor biopsies at 24?h post-UCN-01. Two partial responses were observed in women with ER, PgR, and HER2-negative breast cancers (TBNC). Both tumors were defective for p53. Twelve patients had stable disease (mean duration 18?weeks, range 7?C30?weeks).Conclusion
UCN-01 and irinotecan demonstrated acceptable toxicity and target inhibition. Anti-tumor activity was observed and a study of this combination in women with TNBC is underway. 相似文献10.
Na YS Jung KA Kim SM Hong YS Ryu MH Jang SJ Moon DH Cho DH Kim JC Lee JS Kim TW 《Cancer chemotherapy and pharmacology》2011,68(2):389-398
Purpose
Histone deacetylase inhibitors (HDACIs), such as PXD101 and suberoylanilide hydroxamic acid, inhibit proliferation and stimulate apoptosis of tumor cells. The enhanced effectiveness of chemotherapy or radiotherapy when combined with HDACIs has been observed in several cancers. In this study, we investigated the antitumor effect of PXD101 combined with irinotecan in colon cancer.Methods
HCT116 and HT29 colon cancer cells for cell viability assay were treated with PXD101 and/or SN-38, the active form of irinotecan. Antitumor effects of HCT116 and HT29 xenografts treated with these combinations were evaluated. [18F]FLT-PET was used to detect early responses to PXD101 and irinotecan in colon cancer.Results
PXD101 and SN38 possessed dose-dependent antiproliferative activity against HCT116 and HT29 cells and exerted a synergistic effect when used in combination. In xenografted mice, PXD101 in combination with irinotecan dramatically inhibited tumor growth without causing additive toxicity. Apoptotic effects on xenograft tumors were greater with combined treatment than with irinotecan alone. [18F]FLT-PET imaging revealed a 64% decrease in [18F]FLT uptake in tumors of HCT116 xenograft-bearing mice treated with a combination of PXD101 and irinotecan, indicating a decrease in thymidine kinase 1 (TK1) activity. These results were supported by Western blot analyses showing a decrease in tumor thymidine kinase 1 protein levels, suggesting that [18F]FLT-PET can be used to non-invasively detect early responses to these agents.Conclusions
These data show that PXD101 increases the cytotoxic activity of irinotecan in in vitro and in vivo colon cancer models and suggest these agent combinations should be explored in the treatment of colon cancer. 相似文献11.
W A Teft S Welch J Lenehan J Parfitt Y-H Choi E Winquist R B Kim 《British journal of cancer》2015,112(5):857-865
Background:
Treatment of advanced and metastatic colorectal cancer with irinotecan is hampered by severe toxicities. The active metabolite of irinotecan, SN-38, is a known substrate of drug-metabolising enzymes, including UGT1A1, as well as OATP and ABC drug transporters.Methods:
Blood samples (n=127) and tumour tissue (n=30) were obtained from advanced cancer patients treated with irinotecan-based regimens for pharmacogenetic and drug level analysis and transporter expression. Clinical variables, toxicity, and outcomes data were collected.Results:
SLCO1B1 521C was significantly associated with increased SN-38 exposure (P<0.001), which was additive with UGT1A1*28. ABCC5 (rs562) carriers had significantly reduced SN-38 glucuronide and APC metabolite levels. Reduced risk of neutropenia and diarrhoea was associated with ABCC2–24C/T (odds ratio (OR)=0.22, 0.06–0.85) and CES1 (rs2244613; OR=0.29, 0.09–0.89), respectively. Progression-free survival (PFS) was significantly longer in SLCO1B1 388G/G patients and reduced in ABCC2–24T/T and UGT1A1*28 carriers. Notably, higher OATP1B3 tumour expression was associated with reduced PFS.Conclusions:
Clarifying the association of host genetic variation in OATP and ABC transporters to SN-38 exposure, toxicity and PFS provides rationale for personalising irinotecan-based chemotherapy. Our findings suggest that OATP polymorphisms and expression in tumour tissue may serve as important new biomarkers. 相似文献12.
13.
Kimie Sai Yoshiro Saito Keiko Maekawa Su-Ryang Kim Nahoko Kaniwa Tomoko Nishimaki-Mogami Jun-ichi Sawada Kuniaki Shirao Tetsuya Hamaguchi Noboru Yamamoto Hideo Kunitoh Yuichiro Ohe Yasuhide Yamada Tomohide Tamura Teruhiko Yoshida Yasuhiro Matsumura Atsushi Ohtsu Nagahiro Saijo Hironobu Minami 《Cancer chemotherapy and pharmacology》2010,66(1):95-105
Purpose
Effects of genetic polymorphisms/variations of ABCB1, ABCC2, ABCG2 and SLCO1B1 in addition to “UGT1A1*28 or *6” on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients were investigated.Methods
Associations between transporter haplotypes/variations along with UGT1A1*28 or *6 and SN-38 area under the time–concentration curve (AUC) or neutropenia were examined in irinotecan monotherapy (55 patients) and irinotecan–cisplatin-combination therapy (62 patients).Results
Higher SN-38 AUC values were observed in ABCB1 2677G>T (A893S) (*2 group) for both regimens. Associations of grade 3/4 neutropenia were observed with ABCC2 ?1774delG (*1A), ABCG2 421C>A (Q141K) and IVS12 + 49G>T ( # IIB) and SLCO1B1 521T>C (V174A) (*15 · 17) in the irinotecan monotherapy, while they were evident only in homozygotes of ABCB1*2, ABCG2 # IIB, SLCO1B1*15 · 17 in the cisplatin-combination therapy. With combinations of haplotypes/variations of two or more genes, neutropenia incidence increased, but their prediction power for grade 3/4 neutropenia is still unsatisfactory.Conclusions
Certain transporter genotypes additively increased irinotecan-induced neutropenia, but their clinical importance should be further elucidated. 相似文献14.
Moon Ki Choi Byung-Jin Ahn Dong-Seok Yim Young Suk Park Sung Kim Tae Sung Sohn Jae Hyung Noh Jin Seok Heo Jeeyun Lee Se Hoon Park Joon Oh Park Ho Yeong Lim Won Ki Kang 《Cancer chemotherapy and pharmacology》2011,67(1):5-11
Purpose
The objectives of this phase I study were to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and preliminary efficacy of intraperitoneally administered irinotecan (CPT-11) in gastric cancer patients with peritoneal seeding.Experimental design
Gastric adenocarcinoma patients with surgical biopsy proven peritoneal seeding were enrolled at the time of surgery. Prior to IP chemotherapy, patients underwent palliative gastrectomy and CAPD catheter insertion in which CPT-11 was administered on postoperative day 1. The IP CPT-11 was initiated at 50?mg/m2, which was escalated to 100, 150, 200, 250, and 300?mg/m2. IP CPT-11 chemotherapy was repeated every 3?weeks.Results
Seventeen patients received a total of 56?cycles at five different CPT-11 dose levels. The DLTs were neutropenic fever, neutropenia, and diarrhea. At the dose level 2 (100?mg/m2), there were one DLTs in one of the first cohort of three patients, but no DLTs at the second cohort of this level. At the dose level 5 (250?mg/m2), two DLTs were detected in the first two patients; thus, the accrual was stopped resulting in the recommended dose of IP CPT-11 of 200?mg/m2. Median progression-free survival was 8.6?months (95% CI, 5.9,11.2), and median overall survival was 15.6?months (95% CI, 8.4,22.8). Pharmacokinetic results of the study showed that the C max of peritoneal SN-38 was achieved earlier than that of plasma SN-38.Conclusions
Intraperitoneally administered CPT-11 was feasible and tolerable. Further, phase II study of IP CPT-11 in gastric cancer patients with peritoneal seeding is warranted. 相似文献15.
R. P. Jones P. Sutton R. M. D. Greensmith A. Santoyo-Castelazo D. F. Carr R. Jenkins C. Rowe J. Hamlett B. K. Park M. Terlizzo E. O’Grady P. Ghaneh S. W. Fenwick H. Z. Malik G. J. Poston N. R. Kitteringham 《Cancer chemotherapy and pharmacology》2013,72(2):359-368
Purpose
The response of colorectal liver metastases to the cytotoxic agent irinotecan varies widely. Attempts to correlate tumour metabolism with response have been mixed. This study investigated the hepatic metabolism of irinotecan as a potential predictor of tumour response to irinotecan-eluting beads (DEBIRI).Methods
Ten patients with colorectal liver metastases were treated with 200 mg irinotecan (as DEBIRI) as part of the PARAGON II study. Hepatic expression of key metabolising enzymes was measured using mass spectrometry-based proteomics. Serum drug concentrations and hepatic irinotecan metabolism were characterised and correlated with tumour response.Results
Serum concentrations of irinotecan metabolites did not correlate with hepatic metabolism or pathological response. There was a strong correlation between hepatic CES-2 expression and activation of irinotecan (r 2 = 0.96, p < 0.001). Patients with a UGT1A1*28 6/7 SNP showed no difference in drug metabolism or pathological response. Hepatic CES-2 mediated activation of irinotecan clearly correlated with tumour replacement by fibrosis (r 2 = 0.54, p = 0.01).Conclusion
This study provides the first evidence that hepatic activation of irinotecan predicts tumour response. Delivery of liver-targeted irinotecan to normal liver tissue rather than tumour may be a more rational approach to maximise response. 相似文献16.
Ken-ichi Fujita Minako Sugiyama Yuko Akiyama Yuichi Ando Yasutsuna Sasaki 《Cancer chemotherapy and pharmacology》2011,67(1):237-241
Purpose
Inhibition of the UDP-glucuronosyltransferase (UGT) 1A1 by nilotinib was examined in vitro with SN-38 as a substrate, to estimate the possibility of drug–drug interaction of nilotinib with other medicines predominantly detoxified by UGT1A1.Methods
Inhibition of UGT1A1-catalyzed SN-38 glucuronidation by nilotinib was examined with human liver microsomes (HLM) and recombinant human UGT1A1 as enzyme sources. Inhibition constants (K i) were estimated with kinetic analysis.Results
Nilotinib potently inhibited the SN-38 glucuronidation by human liver microsomal UGT1A1 and recombinant UGT1A1 in a noncompetitive manner, with K i values of 0.286 ± 0.0094 and 0.079 ± 0.0029 μM, respectively. If a drug that serves as a substrate of UGT1A1 is administered with nilotinib, the area under the plasma concentration–time curve of a drug estimated by using these K i values would be two times or higher than that without nilotinib, suggesting drug–drug interactions involving UGT1A1. These in vitro data and the prediction of drug–drug interaction are helpful for the clinical management of the nilotinib use.Conclusion
We found that nilotinib is a potent noncompetitive inhibitor of human UGT1A1 activity. 相似文献17.
Jeffrey R. Infante Vicki L. Keedy Suzanne F. Jones William C. Zamboni Emily Chan Johanna C. Bendell Wooin Lee Huali Wu Satoshi Ikeda Hiroshi Kodaira Mace L. Rothenberg Howard A. Burris III 《Cancer chemotherapy and pharmacology》2012,70(5):699-705
Purpose
IHL-305 is a novel PEGylated liposome containing irinotecan. This study examined the safety profile and pharmacokinetics of IHL-305 and established the maximum tolerated dose and recommended phase II dose (RP2D).Patients and methods
In a standard 3?+?3 design, IHL-305 was administered IV on day 1 of a 28-day treatment schedule. Subsequently, a 14-day treatment schedule was also explored. Two patient populations were evaluated separately: Patients with at least one wild-type (wt) allele of UGT1A1 (UDP glucoronosyltransferase 1A1) wt/wt or wt/*28 as one group (referred to as UGT1A1 wt group) and patients with UGT1A1*28 homozygous variant (*28/*28) as another group.Results
Sixty patients were treated: 42 on the 28-day schedule and 18 on the 14-day schedule. Seven patients were homozygous variant (*28/*28). In the UGT1A1 wt group, the MTD and RP2D of IHL-305 was 160?mg/m2 every 28?days and 80?mg/m2 every 14?days. DLTs included nausea, vomiting, diarrhea, and neutropenia. The most common adverse events were nausea (75?%), vomiting (52?%), diarrhea (62?%), anorexia (57?%), and fatigue (57?%). At the MTD for both schedules, IHL-305 administration resulted in a high and prolonged exposure of sum total irinotecan, released irinotecan, and SN-38 in plasma. One partial response was observed in a patient with breast cancer and eight patients had stable disease for >6?months.Conclusions
IHL-305, a novel preparation of irinotecan encapsulated in liposomes, can be safely given to patients in a repeated fashion on a 4- or 2-week dosing schedule. 相似文献18.
Akira Tsunoda Naokuni Yasuda Kentaro Nakao Kazuhiro Narita Makoto Watanabe Nobuaki Matsui Yuko Tsunoda Mitsuo Kusano 《International journal of clinical oncology / Japan Society of Clinical Oncology》2010,15(3):280-286
Background
We carried out this study to examine the health-related quality of life (HRQOL) of patients with advanced colorectal cancer treated with the oral fluoropyrimidine S-1 plus irinotecan (CPT-11).Methods
HRQOL was assessed at baseline (pretreatment) and at 5-week intervals during treatment, using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 questionnaires. The HRQOL data for 12 preselected scales and 21 courses of treatment were then analyzed longitudinally.Results
Thirty-seven patients completed the baseline and post-treatment HRQOL assessments. Statistically significant differences between the baseline and post-treatment HRQOL scores were observed for the global QOL, social function, and pain scales (all QLQ-C30), as well as the body image, future perspective, gastrointestinal tract symptoms, weight loss, and chemotherapy side effects scales (all QLQ-CR38); favorable post-treatment results were observed for all the scales except for body image and chemotherapy side effects, for which post-treatment deteriorations were observed. The changes in body image, future perspective, weight loss, and chemotherapy side effects were each greater than ten points and seemed clinically significant.Conclusion
Combined treatment with S-1 plus CPT-11 resulted in an acceptable deterioration in HRQOL functioning and symptoms, compared with baseline levels. 相似文献19.
van der Bol JM Loos WJ de Jong FA van Meerten E Konings IR Lam MH de Bruijn P Wiemer EA Verweij J Mathijssen RH 《European journal of cancer (Oxford, England : 1990)》2011,47(6):831-838
Background
Omeprazole is one of the most prescribed medications worldwide and within the class of proton pump inhibitors, it is most frequently associated with drug interactions. In vitro studies have shown that omeprazole can alter the function of metabolic enzymes and transporters that are involved in the metabolism of irinotecan, such as uridine diphosphate glucuronosyltransferase subfamily 1A1 (UGT1A1), cytochrome P-450 enzymes subfamily 3A (CYP3A) and ATP-binding cassette drug-transporter G2 (ABCG2). In this open-label cross-over study we investigated the effects of omeprazole on the pharmacokinetics and toxicities of irinotecan.Methods
Fourteen patients were treated with single agent irinotecan (600 mg i.v., 90 min) followed 3 weeks later by a second cycle with concurrent use of omeprazole 40 mg once daily, which was started 2 weeks prior to the second cycle. Plasma samples were obtained up to 55 h after infusion and analysed for irinotecan and its metabolites 7-ethyl-10-hydroxycampothecin (SN-38), SN-38-glucuronide (SN-38G), 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin (NPC) and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC) by high-performance liquid chromatography (HPLC). Non-compartmental modelling was performed. Toxicities were monitored during both cycles. Paired statistical tests were performed with SPSS.Results
The exposure to irinotecan and its metabolites was not significantly different between both cycles. Neither were there significant differences in the absolute nadir and percentage decrease of WBC and ANC, nor on the incidence and severity of neutropenia, febrile neutropenia, diarrhoea, nausea and vomiting when irinotecan was combined with omeprazole.Conclusion
Omeprazole 40 mg did not alter the pharmacokinetics and toxicities of irinotecan. This widely used drug can, therefore, be safely administered during a 3-weekly single agent irinotecan schedule. 相似文献20.
W Ichikawa K Uehara K Minamimura C Tanaka Y Takii H Miyauchi S Sadahiro K Fujita T Moriwaki M Nakamura T Takahashi A Tsuji K Shinozaki S Morita Y Ando Y Okutani M Sugihara T Sugiyama Y Ohashi Y Sakata 《British journal of cancer》2015,112(10):1709-1716