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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-06-1860. This Article Abstract Full Text (PDF) All Versions of this Article: 2002-06-1860v1 101/5/2043    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by McDonald, G. B. Articles by Gooley, T. Search for Related Content PubMed PubMed Citation Articles by McDonald, G. B. Articles by Gooley, T. Related Collections Transplantation Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 March 2003, Vol. 101, No. 5, pp. 2043-2048 TRANSPLANTATION Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation George B. McDonald, John T. Slattery, Michelle E. Bouvier, Song Ren, Ami L. Batchelder, Thomas F. Kalhorn, H. Gary Schoch, Claudio Anasetti, and Ted Gooley From the Clinical Research Division, Fred Hutchinson Cancer Research Center, and the Departments of Medicine and Pharmaceutics, University of Washington Schools of Medicine and Pharmacy, Seattle, WA.     Abstract Top Abstract Introduction Patients, materials, and... Results Discussion References Liver toxicity caused by high-dose myeloablative therapy leads to significant morbidity after hematopoietic cell transplantation. We examined the hypothesis that liver toxicity after cyclophosphamide and total body irradiation is related to cyclophosphamide through its metabolism to toxins. Cyclophosphamide was infused at 60 mg/kg over 1 to 2 hours on each of 2 consecutive days, followed by total body irradiation. Plasma was analyzed for cyclophosphamide and its major metabolites. Liver toxicity was scored by the development of sinusoidal obstruction syndrome (veno-occlusive disease) and by total serum bilirubin levels. The hazards of liver toxicity, nonrelapse mortality, tumor relapse, and survival were calculated using regression analysis that included exposure to cyclophosphamide metabolites (as the area under the curve). Of 147 patients, 23 (16%) developed moderate or severe sinusoidal obstruction syndrome. The median peak serum bilirubin level through day 20 was 2.6 mg/dL (range, 0.5-41.1 mg/dL). Metabolism of cyclophosphamide was highly variable, particularly for the metabolite o-carboxyethyl-phosphoramide mustard, whose area under the curve varied 16-fold. Exposure to this metabolite was statistically significantly related to sinusoidal obstruction syndrome, bilirubin elevation, nonrelapse mortality, and survival, after adjusting for age and irradiation dose. Patients in the highest quartile of o-carboxyethyl-phosphoramide mustard exposure had a 5.9-fold higher risk for nonrelapse mortality than did patients in the lowest quartile. Engraftment and tumor relapse were not statistically significantly related to cyclophosphamide metabolite exposure. Increased exposure to toxic metabolites of cyclophosphamide leads to increased liver toxicity and nonrelapse mortality and lower overall survival after hematopoietic cell transplantation. (Blood. 2003;101:2043-2048) © 2003 by The American Society of Hematology.     Introduction Top Abstract Introduction Patients, materials, and... Results Discussion References Hematopoietic stem cell transplantation following a myeloablative preparative regimen is the treatment of choice for some patients with refractory hematologic malignancy, aplastic anemia, and certain inborn errors of metabolism.1 A major limitation of myeloablative regimens is damage to the liver and development of multiorgan failure, a cause of death after transplantation.2-4 In the study reported here, we examined the hypothesis that liver toxicity that develops after a conditioning regimen containing cyclophosphamide and total body irradiation (TBI) is related to how cyclophosphamide is metabolized. The genesis of this hypothesis came from 4 observations: (1) cyclophosphamide is a component of the most hepatotoxic myeloablative regimens2,3; (2) in vitro, hepatic sinusoidal endothelial cells are injured by metabolites of cyclophosphamide that are generated within hepatocytes5; (3) damage to the microcirculation of the liver is central to the development of hepatic dysfunction after transplantation2,6-8; (4) there is patient-to-patient variability in cyclophosphamide metabolism and a relation of aberrant metabolism to toxicity in other organs.9-11     Patients, materials, and methods Top Abstract Introduction Patients, materials, and... Results Discussion References Patient selection This was a prospective study of the relationship between cyclophosphamide metabolism and clinical outcome. Between April 1997 and January 2000, all patients with hematologic malignancy undergoing allogeneic transplantation following a preparative regimen of cyclophosphamide (CY) plus total body irradiation were invited to participate. Patients signed informed consent approved by the Institutional Review Board of the Fred Hutchinson Cancer Research Center. Technique of hematopoietic cell transplantation Seven days before the infusion of stem cells, CY was infused through a central venous access catheter over 1 to 2 hours at a dose of 60 mg/kg body weight.12 On the following day, a second infusion of CY was given, at the same dose. After a day of rest, total body irradiation was given on each of the 3 or 4 subsequent days in hyperfractionated doses from opposing cobalt sources. Regimens of prophylaxis against graft-versus-host disease (GVHD) are given in Table 1; BC3 is a murine antibody specific for human CD3.13 Infection prophylaxis included fluconazole or itraconazole, acyclovir, and trimethoprim-sulfamethoxazole.                                View this table: [in this window] [in a new window]   Table 1. Characteristics of 147 patients receiving cyclophosphamide and total body irradiation as myeloablative therapy followed by allogeneic transplantation Measurement of plasma levels of cyclophosphamide and its metabolites Blood samples were removed from a non-CY infusion port of a central venous access catheter before each CY infusion and at the following times: mid-infusion, immediately after the completion of infusion, and at 1, 3, 7, 20, and 24 hours afterward. Aliquots of each sample were placed into tubes containing either p-nitrophenyl hydrazine for analysis of 4-hydroxy cyclophosphamide or EDTA (ethylenediaminetetraacetic acid) for other analytes; then they were mixed and centrifuged at the bedside. Plasma was immediately removed, frozen, and stored at 80°C until analysis.14,15 Exposure to CY metabolites was expressed as the area under the curve (AUC; µM·h) derived from time zero (the time of the first CY dose) to 24 hours after the second dose of CY. The data reflect exposure to CY and its metabolites4-hydroxy-cyclophosphamide (HCY), o-carboxyethyl-phosphoramide mustard (CEPM), deschloroethyl-cyclophosphamide (DCCY), 4-keto-cyclophosphamide (KetoCY), and hydroxypropyl-phosphoramide mustard (HPPM) (Figure 1). View larger version (10K): [in this window] [in a new window]   Figure 1. Quantitative disposition of cyclophosphamide (CY) indicating fraction of dose eliminated by pathway. Chloroacetaldehyde (CAA), acrolein, and phosphoramide mustard (PM) are cytotoxins, but acrolein and PM are the major toxins because of the abundance of their formation. HCY (4-hydroxy-cyclophosphamide) is formed primarily in the liver but circulates in blood, entering cells as its tautomer aldocyclophosphamide (AldoCY). Acrolein and PM are formed from AldoCY when it decomposes through -elimination. Other metabolites include o-carboxyethyl-phosphoramide mustard (CEPM), deschloroethyl-cyclophosphamide (DCCY), 4-keto-cyclophosphamide (KetoCY), hydroxypropyl-phosphoramide mustard (HPPM), imino-cyclophosphamide (IminoCy), and glutathionyl-cyclophosphamide (GSCY). Definition of liver toxicity Liver toxicity was scored by categoric and continuous variablesthat is, the presence or absence of sinusoidal obstruction syndrome (SOS)2,7,8 and frequent measurement of total serum bilirubin levels through day 20 after transplantation. In patients who have undergone transplantation, SOS is an anatomically precise term for a clinical syndrome caused by toxin injury to hepatic sinusoids, conventionally described by the generic name veno-occlusive disease.6,8 SOS is our preferred term because hepatic venules are frequently patent in patients with this syndrome and because damage to sinusoidal endothelial cells is the initiating event.6,8 In the current study, a diagnosis of SOS was based on development of hepatomegaly, weight gain, and jaundice before day 20, as described previously.2 The severity of SOS was classified according to the subsequent course of the disease as mild (clinically obvious, requires no treatment, and resolves completely), moderate (causes signs and symptoms requiring treatment, such as diuretics or pain medications, but resolves completely), or severe (requires treatment but does not resolve before death or day 100).2,3,16 Patients without evidence of liver disease were categorized as not having SOS, and patients in whom liver disease developed before day 20 after transplantation but that did not meet the criteria for SOS (for example, acute graft-versus-host disease and cholangitis lenta17) were categorized as having liver disease of unknown etiology, as previously described.2 Total serum bilirubin level was quantified in all patients in the study cohort as the maximum value between day 0 and day 20 and as the average daily bilirubin level, without reference to cause of hyperbilirubinemia. Assessment of liver toxicity was made without knowledge of cyclophosphamide pharmacokinetics. Statistical methods The primary end point of this prospective study was liver toxicity; secondary end points included nonrelapse mortality, relapse, engraftment, and overall survival. The study was designed to enroll 200 patients. If the true effect size, or the difference in means divided by standard deviation, for the AUC of a specified metabolite is 0.75, this number (200 patients) allows 94% power to detect a statistically significant difference in AUC at the 2-sided P = .05 significance level between patients with no SOS and patients with moderate to severe SOS. An interim analysis conducted after 140 patients were enrolled showed that significant differences had been demonstrated; thus, the study was stopped when this information became available, after 147 patients had been enrolled. The probability of survival was estimated using the Kaplan-Meier method, and the probabilities of nonrelapse mortality and relapse were summarized using cumulative incidence estimates. Relapse was regarded as a competing risk for nonrelapse mortality, and death without relapse was considered a competing risk for relapse. Liver toxicity as a categorical variable termed sinusoidal obstruction syndrome was assessed using logistic regression and as a continuous variable (total serum bilirubin) using linear regression. The hazards of overall mortality, nonrelapse mortality, and relapse were assessed using proportional hazards regression. For each of these end points, a base model was fit from among variables not including the pharmacokinetic parametersthat is, age, sex, diagnosis, dose of irradiation, and pretransplantation laboratory values for serum aspartate aminotransferase, albumin, creatinine, and blood urea nitrogen. Once the appropriate base model was fit, the model additionally containing one of the pharmacokinetic parameters was compared to the base model using the likelihood ratio test. Spearman rank correlation coefficient was used to assess the association between days to engraftment (by various measures) and pharmacokinetic parameters. All reported P values were 2-sided, and those estimated from regression models were derived from the Wald test. Several measures of liver toxicity were used, and these measures were obviously correlated. In addition, several metabolites of cyclophosphamide were measured, and some of these are correlated as well. It is, therefore, difficult to know how to best adjust for multiple comparisons in the estimation of reported P values, and for this reason no adjustments were made. P values between .01 and .05 should be considered suggestive of a true difference, particularly for secondary end points.     Results Top Abstract Introduction Patients, materials, and... Results Discussion References Characteristics of the study cohort The study cohort comprised 147 patients, 73 who underwent transplantation for chronic myeloid leukemia in chronic phase (CML-CP) and 74 who underwent it for other forms of hematologic malignancy (Table 1). For 139 patients, hematopoietic stem cells were from unrelated donors. Frequency of liver toxicity through day 20 Of 147 patients studied, 56 (38%) had clinical criteria for SOS; 10 had severe, 13 had moderate, and 33 had mild liver disease. Seventy-six (51%) patients had no evidence of SOS. Fifteen patients were classified as having liver disease of uncertain etiology. The median value for maximum daily total serum bilirubin level through day 20 was 2.6 mg/dL (range, 0.5-41.1 mg/dL). The median value for average daily total serum bilirubin level through day 20 was 1.4 mg/dL (range, 0.4-13.0 mg/dL). Cyclophosphamide metabolite exposure and liver toxicity Variability of exposure (expressed as the AUC) to CY was 3.3 ×, but that of metabolites was higher, from 7.8 × for HCY, to 8.0 × for DCCY, to 16.1 × for CEPM. Data for exposure of patients to CY and its metabolites, according to the clinical diagnosis and severity of SOS, are given in Table 2.                                View this table: [in this window] [in a new window]   Table 2. AUCs for cyclophosphamide and its metabolites, expressed as µM·h Among patients with no SOS or with moderate to severe SOS, a logistic regression model was fit to model the probability of moderate to severe SOS. After adjusting for age at transplantation and dose of irradiation (1200 or less vs more than 1200 cGy TBI), the model additionally containing AUCCEPM was statistically significantly improved compared with the model without AUCCEPM (P = .007); the model additionally containing AUCCY was suggestively improved (P = .04). Moreover, among all 147 patients, increasing AUCCEPM was statistically significantly associated with an increased maximum total serum bilirubin level before day 20 (P = .0001) and average daily total serum bilirubin level before day 20 (P = .0001) after adjusting for age and conditioning regimen. Increasing AUCCY was also associated with each of these bilirubin parameters, but the association was not as strong as seen with AUCCEPM (P = .01 and P = .04, respectively). Cyclophosphamide pharmacokinetics and relation to nonrelapse mortality Figure 2 shows estimates of the probability of nonrelapse mortality according to quartiles of CEPM exposure. After adjusting for age at transplantation and type of disease (CML-CP vs other diagnoses), the hazard of nonrelapse mortality increased as CEPM exposure increased (P < .001). Summarized in Table 3 are the results from a multivariable proportional hazards regression model with AUCCEPM as a categorical variable. Addition of AUCCY (as a continuous variable) to the model containing age and disease did not lead to a statistically significant improvement in the model (P = .32). View larger version (17K): [in this window] [in a new window]   Figure 2. Cumulative incidence estimates of the probability of nonrelapse mortality. Estimates are displayed as a function of exposure to the cyclophosphamide metabolite, CEPM, expressed as the lowest (first) quartile through the highest (fourth) quartile of AUCCEPM.                                View this table: [in this window] [in a new window]   Table 3. Regression model of the relation of CEPM exposure to the hazard of nonrelapse mortality, adjusted for the variables age at transplantation and disease Cyclophosphamide pharmacokinetics and engraftment of neutrophils and platelets Although higher exposure to the metabolite CEPM was associated with increased liver toxicity and nonrelapse mortality, it is also possible that exposure to higher toxin levels could benefit patients by ensuring engraftment or preventing relapse. To test these possibilities, we next examined the Spearman rank correlation of AUCs for CEPM, HCY, and CY for the outcome variables time to sustained ANC greater than 1000/mm3 and time to sustained platelet count greater than 20 000/mm3. No statistically significant correlations were found for any of the CY metabolite exposures (data not shown). Moreover, most of the observed correlations were positive (ie, the higher the AUC, the longer the time to engraftment). Among 7 patients in whom engraftment was not successful, the median AUCCEPM was 442 µM·h, compared with a median AUCCEPM of 390 µM·h among 138 patients who did achieve a sustained ANC of more than 500/mm3. The median AUCHCY among the 7 patients who did not engraft was 108 µM·h compared with 142 µM·h among the 140 patients who did engraft. Although this difference is not statistically significant (P = .43, Wilcoxon rank-sum test), the possibility exists that the low number of patients who did not engraft precludes such a difference from being detected. Cyclophosphamide metabolite exposure and tumor relapse Twenty-nine relapses occurred. We examined the relation between CY metabolite exposure and relapse in the group of 147 as a whole, in a cohort of 73 patients with CML-CP, and in a cohort of 74 patients with malignancies other than CML-CP. If AUCCEPM (and its logarithm) are modeled as continuous variables in a multivariable Cox regression model for relapse (adjusting for disease [CML-CP vs other diagnoses] and age), AUCCEPM showed no suggestion of an association with the hazard of relapse (P = .88 and P = .75, respectively). If AUCCEPM is modeled in quartiles, the following is seen: hazard ratio (HR) = 1.9 for Q2 versus Q1; HR = 0.5 for Q3 versus Q1; HR = 1.3 for Q4 versus Q1. If AUCHCY (and its logarithm) are modeled as continuous variables, the adjusted hazards of relapse are actually increased as AUCHCY increases (P = .19 for each parameter). Finally, if AUCCY (and its logarithm) are modeled as continuous variables, AUCCY shows no suggestion of an association with the adjusted hazards of relapse (P = .64 and P = .46, respectively). If one restricts the analysis to CML-CP patients only (n = 73), there were only 7 relapses among this group, so it is not likely that any statistically significant associations could be seen. As shown in Table 4, among the few CML-CP patients who did experience relapse, there does not appear to be any obvious differences in exposure to CY or its metabolites HCY and CEPM compared with the CML-CP patients who did not experience relapse. We also examined the relationship between exposure to CEPM, HCY, and CY and relapse in the cohort of 74 patients with malignancies other than CML-CP and found no significant associations for any metabolite.                                View this table: [in this window] [in a new window]   Table 4. Exposure to cyclophosphamide and its metabolites CEPM and HCY in relation to relapse of hematologic malignancy after transplantation Cyclophosphamide metabolite exposure and overall survival Figure 3 shows estimates of overall survival according to quartiles of AUCCEPM. View larger version (17K): [in this window] [in a new window]   Figure 3. Kaplan-Meier estimates of the probability of overall survival. Data are displayed as a function of exposure to the cyclophosphamide metabolite, CEPM, expressed as the lowest (first) quartile through the highest (fourth) quartile of AUCCEPM. If AUCCEPM is modeled as a continuous variable and added to the regression model containing age and disease, the resultant model is statistically significantly improved (P = .002, likelihood ratio test). Inclusion of AUCCY as a continuous variable, however, does not lead to a statistically significant improved model over that containing age and disease (P = .20). Table 5 summarizes results from the multivariable regression model with AUCCEPM modeled as quartiles.                                View this table: [in this window] [in a new window]   Table 5. Regression model of the relation of CEPM exposure to the hazard of overall mortality, adjusted for the variables age at transplantation and disease     Discussion Top Abstract Introduction Patients, materials, and... Results Discussion References The primary objective of this study was to assess the impact of cyclophosphamide metabolism on liver toxicity caused by the preparative regimen. We found that increased exposure to toxic metabolites of cyclophosphamide led to increased liver toxicity and mortality and to decreased survival. Patients who had the lowest exposures to the metabolites CEPM and HCY were not at increased risk for failure to engraft or for relapse of malignancy. These results suggest that the dose of CY in the CY-TBI preparative regimen can be reduced without jeopardizing either engraftment or any antitumor effects of this preparative regimen. The toxic metabolites formed after the administration of CY are acrolein and phosphoramide mustard.18-21 HCY is a protoxic metabolite converted to the actual toxins by the single step of -elimination. Because CEPM is a nontoxic product of oxidation of HCY/aldophosphamide by ALHD1A1,22,23 our finding of a strong positive correlation between AUCCEPM and liver injury is the opposite of what might have been expected. Indeed, the formation of CEPM from HCY putatively explains the relative resistance of early hematopoietic precursors and L1210 leukemia cells from injury after the administration of CY.24-26 To verify that CEPM was not a hepatotoxin, we conducted incubations of CY, HCY, and CEPM with rat liver slices. CEPM was not toxic at millimolar concentrations, whereas CY and HCY were toxic at micromolar concentrations (S.R., J.T.S., unpublished observations, June 1999)that is, CY and HCY were toxic because they were converted to the toxins acrolein and phosphoramide mustard. CEPM is the only chemically stable major CY metabolite formed between the activation of CY to HCY and the ultimate formation of glutathione conjugates of acrolein and phosphoramide mustard. The obvious hypothesis is that CEPM reports on the intrahepatocellular (or intrahepatic) exposure to chemically reactive species formed from HCY. However, for this to be so, there must be a means by which the intrahepatocellular AUCCEPM correlates positively with the intrahepatocellular AUCHCY, because the action of ALDH1A1 would produce a negative correlation. A positive correlation between the intrahepatocellular AUCCEPM and AUCHCY requires a route of elimination of HCY that competes with the formation of CEPM (Figure 1). Most likely this requirement is fulfilled by the transport of glutathionyl-cyclophosphamide (GSCY) out of the hepatocyte by the bile canalicular multiorganic anion transporter ABCC2, which has been shown to transport glutathione conjugates.27 Preliminary studies in Wistar rats and TR rats (lacking ABCC2 expression in canalicular membranes) support the hypothesis that GSCY is a substrate of ABCC2: TR rats have higher AUCCEPM and greater hepatic GSCY and HCY than do wild-type Wistar rats (R. Qiu, J.T.S., unpublished observations, June 2001). The initial site of injury following high-dose myeloablative therapy and similar toxins is the hepatic sinusoid, specifically dissection of sinusoidal endothelial cells off the sinusoidal basement membrane and widespread hemorrhage in the centrilobular zone of the liver lobule.8,28,29 Cyclophosphamide alone is insufficient to produce the extensive sinusoidal injury that can be seen following cyclophosphamide and total body irradiation.30-32 Total body irradiation, when used alone in doses of 12 to 15 Gy, does not cause significant liver injury.33-35 However, cyclophosphamide followed by TBI is clearly synergistic. There are 2 potential mechanisms: one involves a 2-step injurysublethal damage to sinusoidal endothelial cells caused by cyclophosphamide metabolites followed by irradiation damage. An alternative but not mutually exclusive mechanism involves depletion of reduced glutathione in hepatocytes and sinusoidal endothelial cells by cyclophosphamide, leaving sinusoidal endothelial cells more vulnerable to damage by irradiation. In animals exposed to hepatic irradiation or cyclophosphamide or monocrotaline, liver damage is enhanced by glutathione depletion and is lessened by repletion.5,29,34,36-38 There are several approaches to reducing the mortality caused by the CY-TBI regimen. One is to develop a method to adjust the second dose of CY based on the first day's exposure to the reporter molecule CEPMto target the total exposure to CEPM to a value consistent with low toxicity and reliable engraftment. We estimate that elimination of liver toxicity by metabolism-based CY dosing in patients receiving CY-TBI would reduce nonrelapse deaths after transplantation by 20%. Patients with CML in chronic phase, for which we have the most data showing that CY metabolite exposures are unrelated to engraftment and relapse, are the best candidates for CY dosing that is targeted to a patient's metabolism. A similar targeting strategy has been used in the dosing of busulfan in the busulfan-cyclophosphamide conditioning regimen.39,40 The results of the current study cannot be extrapolated to other CY-containing regimens, such as busulfan-cyclophosphamide, without proof that there is a relation between CY metabolites and the end points toxicity, nonrelapse mortality, and survival following regimens other than CY-TBI. Another approach is to reduce the dose of CY for all patients who are receiving CY-TBI, but this may lead to failed engraftment and graft rejection and, possibly, to increased tumor recurrence. A third approach is to substitute for CY another agent of comparable immunosuppressive and antitumor activity that is not liver toxic.     Acknowledgments We thank Linda Risler, Scott Cole, Rudy Linterman, Scott McDonald, Steven Ellis, and Raymond Salazar for their assistance and the medical and nursing staffs, patients, and patient families for their support. Dr Fred Appelbaum provided a critical review of the manuscript.     Footnotes Submitted June 24, 2002; accepted October 5, 2002. Prepublished online as Blood First Edition Paper, October 24, 2002; DOI 10.1182/blood-2002-06-1860. Supported by grants CA18029 and CA15704 from the National Institutes of Health, National Cancer Institute. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: George B. McDonald, Gastroenterology/Hepatology Section (D2-190), Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109-1024.     References Top Abstract Introduction Patients, materials, and... Results Discussion References 1. Thomas ED, Blume KG, Forman SJ. Hematopoietic cell transplantation. 2nd ed. Cambridge, MA: Blackwell Scientific Publications; 1999. 2. McDonald GB, Hinds MS, Fisher LB, et al. Venocclusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118:255-267[Abstract/Free Full Text]. 3. Carreras E, Bertz H, Arcese W, et al. Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: a prospective cohort study of the European Group for Blood and Marrow Transplantation. Blood. 1998;92:3599-3604[Abstract/Free Full Text]. 4. Rubenfeld GD, Crawford SW. Withdrawing life support from mechanically ventilated recipients of bone marrow transplants: a case for evidence-based guidelines. Ann Intern Med. 1996;125:625-633[Abstract/Free Full Text]. 5. DeLeve LD, Wang XD, Huybrechts MM. Cellular target of cyclophosphamide toxicity in the murine liver: role of glutathione and site of metabolic activation. Hepatology. 1996;24:830-837[CrossRef][Medline] [Order article via Infotrieve]. 6. Shulman HM, Fisher LB, Schoch HG, Henne KW, McDonald GB. Venocclusive disease of the liver after marrow transplantation: histologic correlates of clinical signs and symptoms. Hepatology. 1994;19:1171-1180[CrossRef][Medline] [Order article via Infotrieve]. 7. Jones RJ, Lee KS, Beschorner WE, et al. Veno-occlusive disease of the liver following bone marrow transplantation. Transplantation. 1987;44:778-783[Medline] [Order article via Infotrieve]. 8. Deleve LD, Shulman HM, McDonald GB. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (venocclusive disease). Semin Liver Dis. 2002;22:27-41[CrossRef][Medline] [Order article via Infotrieve]. 9. Ayash LJ, Wright JE, Tretyakov O, et al. Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and tumor response. J Clin Oncol. 1992;10:995-1000[Abstract]. 10. Braverman AC, Antin JH, Plappert MT, Cook EF, Lee RT. Cyclophosphamide cardiotoxicity in bone marrow transplantation: a prospective evaluation of new drug dosing regimens. J Clin Oncol. 1991;9:1215-1223[Abstract]. 11. Chen TL, Passos-Coelho JL, Noe DA. Nonlinear pharmacokinetics of cyclophosphamide in patients with metastatic breast cancer receiving high-dose chemotherapy followed by autologous bone marrow transplantation. Cancer Res. 1995;55:810-816[Abstract/Free Full Text]. 12. Hansen JA, Gooley TA, Martin PJ, et al. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med. 1998;338:962-968[Abstract/Free Full Text]. 13. Anasetti C, Martin PJ, Storb R, et al. Treatment of graft-versus-host disease with a nonmitogenic anti-CD3 monoclonal antibody. Transplantation. 1992;54:844-851[Medline] [Order article via Infotrieve]. 14. Ren S, Kalhorn TF, McDonald GB, Anasetti C, Appelbaum FR, Slattery JT. Pharmacokinetics of cyclophosphamide and its metabolites in bone marrow transplantation patients. Clin Pharmacol Ther. 1998;64:289-301[CrossRef][Medline] [Order article via Infotrieve]. 15. Kalhorn TF, Ren S, Howald WN, Lawrence RF, Slattery JT. Analysis of cyclophosphamide and five metabolites from human plasma using liquid chromatography-mass spectrometry and gas chromatography-nitrogen-phosphorus detection. J Chromatogr B Biomed Sci Appl. 1999;732:287-298[CrossRef][Medline] [Order article via Infotrieve]. 16. McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED. The clinical course of 53 patients with veno-occlusive disease of the liver after marrow transplantation. Transplantation. 1985;36:603-608[CrossRef]. 17. Strasser SI, McDonald GB. Hepatobiliary complications of hematopoietic cell transplantation. In: Schiff ER,Sorrell MF,Maddrey WC, eds. Schiff's Diseases of the Liver. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:1636-1663. 18. Colvin M, Padgett CA, Fenselau C. A biologically active metabolite of cyclophosphamide. Cancer Res. 1973;33:915-918[Abstract/Free Full Text]. 19. Connors TA, Cox PJ, Farmer PB, Foster AB, Jarman M. Some studies of the active intermediates formed in the microsomal metabolism of cyclophosphamide and isophosphamide. Biochem Pharmacol. 1974;23:115-129[CrossRef][Medline] [Order article via Infotrieve]. 20. Struck RF, Kirk MC, Witt MH, Laster WR Jr. Isolation and mass spectral identification of blood metabolites of cyclophosphamide: evidence for phosphoramide mustard as the biologically active metabolite. Biomed Mass Spectrom. 1975;2:46-52[CrossRef][Medline] [Order article via Infotrieve]. 21. Ren S, Yang J-S, Kalhorn TF, Slattery JT. Oxidation of cyclophosphamide to 4-hydroxycyclophosphomide and deschloroethylcyclophosphamide in human liver microsomes. Cancer Res. 1997;57:4229-4235[Abstract/Free Full Text]. 22. Struck RF, Kirk MC, Mellett LB, el Dareer S, Hill DL. Urinary metabolites of the antitumor agent cyclophosphamide. Mol Pharmacol. 1971;7:519-529[Abstract/Free Full Text]. 23. Sladek NE. Bioassay and relative cytotoxic potency of cyclophosphamide metabolites generated in vitro and in vivo. Cancer Res. 1973;33:1150-1158[Abstract/Free Full Text]. 24. Hilton J. Role of aldehyde dehydrogenase in cyclophosphamide-resistant L1210 leukemia. Cancer Res. 1984;44:5156-5160[Abstract/Free Full Text]. 25. Sladek NE, Landkamer GJ. Restoration of sensitivity to oxazaphosphorines by inhibitors of aldehyde dehydrogenase activity in cultured oxazaphosphorine-resistant L1210 and cross-linking agent-resistant P388 cell lines. Cancer Res. 1985;45:1549-1555[Abstract/Free Full Text]. 26. Kohn FR, Sladek NE. Effects of aldehyde dehydrogenase inhibitors on the ex vivo sensitivity of murine late spleen colony-forming cells (day-12 CFU-S) and hematopoietic repopulating cells to mafosfamide (ASTA Z 7557). Biochem Pharmacol. 1987;36:2805-2811[CrossRef][Medline] [Order article via Infotrieve]. 27. Konig J, Nies AT, Cui Y, Leier I, Keppler D. Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP-2 mediated drug resistance. Biochim Biophys Acta. 1999;1461:377-394[Medline] [Order article via Infotrieve]. 28. DeLeve LD, McCuskey RS, Wang X, et al. Characterization of a reproducible rat model of hepatic veno-occlusive disease. Hepatology. 1999;29:1779-1791[CrossRef][Medline] [Order article via Infotrieve]. 29. Wang X, Kanel GC, DeLeve LD. Support of sinusoidal endothelial cell glutathione prevents hepatic veno-occlusive disease in the rat. Hepatology. 2000;31:428-434[CrossRef][Medline] [Order article via Infotrieve]. 30. Clelland BD, Pokorny CS. Cyclophosphamide related hepatotoxicity. Aust N Z J Med. 1993;23:408[Medline] [Order article via Infotrieve]. 31. Modzelewski JR, Daeschner C, Joshi VV, Mullick FG, Ishak KG. Veno-occlusive disease of the liver induced by low dose cyclophosphamide. Mod Pathol. 1994;7:967-972[Medline] [Order article via Infotrieve]. 32. Honjo I, Suou T, Hirayama C. Hepatotoxicity of cyclophosphamide in man: pharmacokinetic analysis. Res Commun Chem Pathol Pharmacol. 1988;61:149-165[Medline] [Order article via Infotrieve]. 33. Fajardo LF, Colby TV. Pathogenesis of veno-occlusive liver disease after radiation. Arch Pathol Lab Med. 1980;104:584-588[Medline] [Order article via Infotrieve]. 34. Geraci JP, Mariano MS, Jackson KL. Radiation hepatopathy of the rat: microvascular fibrosis and enhancement of liver dysfunction by diet and drugs. Radiat Res. 1992;129:322-332[CrossRef][Medline] [Order article via Infotrieve]. 35. Jirtle RL, McLain JR, Strom SC, Michalopoulos G. Repair of radiation damage in noncycling parenchymal hepatocytes. Br J Radiol. 1982;55:847-851[Abstract/Free Full Text]. 36. Teicher BA, Crawford JM, Holden SA, et al. Glutathione monoethyl ester can selectively protect liver from high dose BCNU or cyclophosphamide. Cancer. 1988;62:1275-1281[CrossRef][Medline] [Order article via Infotrieve]. 37. DeLeve LD. Glutathione defense in non-parenchymal cells. Semin Liver Dis. 1998;18:403-413[Medline] [Order article via Infotrieve]. 38. Shulman HM, Luk K, Deeg HJ, Shuman WB, Storb R. Induction of hepatic veno-occlusive disease in dogs. Am J Pathol. 1987;126:114-125[Abstract]. 39. Slattery JT, Clift RA, Buckner CD, et al. Marrow transplantation for chronic myeloid leukemiathe influence of plasma busulfan levels on the outcome of transplantation. Blood. 1997;89:3055-3060[Abstract/Free Full Text]. 40. Yeager AM, Wagner JE Jr, Graham ML, Jones RJ, Santos GW. Optimization of busulfan dosage in children undergoing bone marrow transplantation: a pharmacokinetic study of dose escalation. Blood. 1992;80:2425-2428[Abstract/Free Full Text]. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. W. Saif, A. Choma, S. J. Salamone, and E. Chu Pharmacokinetically Guided Dose Adjustment of 5-Fluorouracil: A Rational Approach to Improving Therapeutic Outcomes J Natl Cancer Inst, October 19, 2009; (2009) djp328v1. [Abstract] [Full Text] [PDF] D. H. 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