Oxazaphosphorines: New therapeutic strategies for an old class of drugs

Expert Opinion on Drug Metabolism and Toxicology

Volumn 6, Issue 8, 2010, Pages 919-938

  Giraud, Bérénice ^a   Hebert, Guillaume ^a   Deroussent, Alain ^a   Veal, Gareth J ^b   Vassal, Gilles ^a   Paci, Angelo ^a  

^a INSTITUT GUSTAVE ROUSSY   (France)

^b NEWCASTLE UNIVERSITY   (United Kingdom)

Author keywords

Alkylating agents; Anticancer drugs; Cancer; Cyclophosphamide; Ifosfamide; Oxazaphosphorine

Indexed keywords

4 METHOXY CYCLOPHOSPHAMIDE; 4 METHOXY IFOSFAMIDE; ACETYLCYSTEINE; ACROLEIN; ANTIDOTE; AZIRIDINE; BLEOMYCIN; CARBOCISTEINE; CHLOROACETALDEHYDE; CISPLATIN; CYCLOPHOSPHAMIDE; CYTOCHROME P450 INHIBITOR; DOXORUBICIN; EPIRUBICIN; ETOPOSIDE; FLUOROURACIL; GLUCOSE DEHYDROGENASE; GLUFOSFAMIDE; GLUTATHIONE; IFOSFAMIDE; MAFOSFAMIDE; MESNA; METHOTREXATE; METHYLENE BLUE; NAVELBINE; OXAZAPHOSPHORINE; PACLITAXEL; TAXANE DERIVATIVE; TROFOSFAMIDE; UNCLASSIFIED DRUG; UNINDEXED DRUG; ALKYLATING AGENT; CYTOCHROME P450;

ABDOMINAL PAIN; ALKYLATION; ALOPECIA; ANTINEOPLASTIC ACTIVITY; BOLUS INJECTION; BREAST CANCER; BREAST CARCINOMA; BREAST METASTASIS; CARDIOTOXICITY; CONFUSION; CONTINUOUS INFUSION; DIZZINESS; DRUG CYTOTOXICITY; DRUG DELIVERY SYSTEM; DRUG DETOXIFICATION; DRUG MEGADOSE; DRUG METABOLISM; DRUG TRANSFORMATION; EWING SARCOMA; GENE THERAPY; GLIOMA; HEADACHE; HEMATURIA; HEMORRHAGIC CYSTITIS; HUMAN; HYDROXYLATION; IMMUNOMODULATION; LEUKOPENIA; LUNG CARCINOMA; LUNG NON SMALL CELL CANCER; LUNG SMALL CELL CANCER; METHEMOGLOBINEMIA; MITOCHONDRIAL TOXICITY; NAUSEA; NAUSEA AND VOMITING; NEPHROTOXICITY; NEUROTOXICITY; NONHODGKIN LYMPHOMA; OVARY CANCER; OVARY CARCINOMA; PRECORDIAL PAIN; PROSTATE CARCINOMA; RENAL PROTECTION; REVIEW; SIDE EFFECT; SINGLE DRUG DOSE; SOFT TISSUE CANCER; SWEATING; UNSPECIFIED SIDE EFFECT; ANALOGS AND DERIVATIVES; ANIMAL; DRUG DESIGN; METABOLISM; NEOPLASMS; PATHOPHYSIOLOGY; PROCEDURES;

ANIMALS; ANTINEOPLASTIC AGENTS, ALKYLATING; CYCLOPHOSPHAMIDE; CYTOCHROME P-450 ENZYME SYSTEM; DRUG DELIVERY SYSTEMS; DRUG DESIGN; GENE THERAPY; HUMANS; IFOSFAMIDE; NEOPLASMS; GENETIC THERAPY;

EID: 77954843368     PISSN: 17425255     EISSN: None     Source Type: Journal    
DOI: 10.1517/17425255.2010.487861     Document Type: Review

References (160)

1. Lehmann-Che J, André F, Desmedt C, et al. Cyclophosphamide dose intensification may circumvent anthracycline resistance of p53 mutant breast cancers. Oncologist 2010;15(3):246-252
2. Sarosy GA, Hussain MM, Seiden MV, et al. Ten-year follow-up of a Phase II study of dose-intense paclitaxel with cisplatin and cyclophosphamide as initial therapy for poor-prognosis, advanced-stage epithelial ovarian cancer. Cancer 2010;116(6):1476-1484
3. Garcia AA, Hirte H, Fleming G, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital Phase II consortia. J Clin Oncol 2008;26(1):76-82
4. Boddy AV, Yule SM. Metabolism and pharmacokinetics of oxazaphosphorines. Clin Pharmacokinet 2000;6(4):291-304
5. Teicher BA, Cucchi CA, Lee JB, et al. In vitro studies of crossresistance patterns in human cell lines. Cancer Res 1986;46:4379-4383
6. Lilley ER, Rosenberg MC, Elion GB, et al. Synergistic interactions between cyclophosphamide or melphalan and VP-16 in a human rhabdomyosarcoma xenograft. Cancer Res 1990;15:284-287
7. Boos J, Silies H, Hohenlochter B. Short-term versus continuous infusion: no influence on ifosfamide side-chain metabolism. Eur J Cancer 1995;31A:2417-2418
8. Fraiser LH, Kanekal S, Kehrer JP. Cyclophosphamide toxicity. Characterising and avoiding the problem. Drugs 1991;42(5):781-795
9. Salminen E, Nikkanen V, Lindholm L. Palliative chemotherapy in non-Hodgkin's lymphoma. Oncology 1997;54(2):108-111
10. Latz D, Nassar N, Frank R. Trofosfamide in the palliative treatment of cancer: a review of the literature. Onkologie 2004;27(6):572-576
11. Stoelting S, Trefzer T, Kisro J, et al. Low-dose oral metronomic chemotherapy prevents mobilization of endothelial progenitor cells into the blood of cancer patients. In Vivo 2008;22:831-836
12. Atzpodien J, Morawek L, Fluck M, Reitz M. Bleomycin, vinorelbine and trofosfamide in relapsed stage IV cutaneous malignant melanoma patients. Cancer Chemother Pharmacol 2009;64(5):901-905
13. Estlin EJ, Veal GJ. Clinical and cellular pharmacology in relation to solid tumours of childhood. Cancer Treat Rev 2003;29(4):253-273
14. Stresser DM, Kupfer D. Monospecific antipeptide antibody to cytochrome P-450 2B6. Drug Metab Dispos 1999;27(4):517-525
15. Gibson GG, Plant NJ, Swales KE, et al. Receptor-dependent transcriptional activation of cytochrome P4503A genes: induction mechanisms, species differences and interindividual variation in man. Xenobiotica 2002;32:165-206
16. Liang J, Huang M, Duan W, et al. Design of new oxazaphosphorine anticancer drugs. Curr Pharm Des 2007;13(9):963-978
17. Chang TKH, Weber GF, Crespi CL, Waxman DJ. Differential activation of cyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in human liver microsomes. Cancer Res 1993;53:5629-5637
18. Roy P, Yu LJ, Crespi CL, Waxman DJ. Development of a substrate-activity based approach to identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos 1999a;27(6):655-666
19. Walker D, Flinois JP, Monkman SC, et al. Identification of the major human hepatic cytochrome P450 involved in activation and N-dechloroethylation of ifosfamide. Biochem Pharmacol 1994;47:1157-1163
20. Boddy AV, Furtun Y, Sardas S, et al. Individual variation in the activation and inactivation of metabolic pathways of cyclophosphamide. J Natl Cancer Inst 1992;84:1744-1748
21. Paci A, Martens T, Royer J. Anodic oxidation of ifosfamide and cyclophosphamide: a biomimetic metabolism model of the oxazaphosphorinane anticancer drugs. Bioorg Med Chem Lett 2001;11:1347-1349
22. Boos J, Küpker F, Blaschke G, Jürgens H. Trofosfamide metabolism in different species-ifosfamide is the predominant metabolite. Cancer Chemother Pharmacol 1993;33(1):71-76
23. Preiss R, Baumann F, Stefanovic D, et al. Investigations on the pharmacokinetics of trofosfamide and its metabolites-first report of 4-hydroxy-trofosfamide kinetics in humans. Cancer Chemother Pharmacol 2004;53(6):496-502
24. Fenselau C, Kan MN, Rao SS, et al. Identification of aldophsophamide as a metabolite of cyclophosphamide in vitro and in vivo in humans. Cancer Res 1977;37:2538-2543
25. Sladek N. Metabolism of oxazaphosphorines. Pharmacol Ther 1988;37:301-355
26. Shulman-Roskes EM, Noe DA, Gamcsik MP, et al. The partitioning of phosphoramide mustard and its aziridinium ions among alkylation and P-N bond hydrolysis reactions. J Med Chem 1998;41(4):515-529
27. Flowers JL, Ludeman SM, Gamcsik MP, et al. Evidence for a role of chloroethylaziridine in the cytotoxicity of cyclophosphamide. Cancer Chemother Pharmacol 2000;45(4):335-344
28. Millis KK, Colvin ME, Shulman-Roskes EM, et al. Comparison of the protonation of isophosphoramide mustard and phosphoramide mustard. J Med Chem 1995;38(12):2166-2175
29. Gamcsik MP, Ludeman SM, Shulman-Roskes EM, et al. Protonation of phosphoramide mustard and other phosphoramides. J Med Chem 1993;36(23):3636-3645
30. Lu H, Chan KK. Pharmacokinetics of N-2-chloroethylaziridine, a volatile cytotoxic metabolite of cyclophosphamide, in the rat. Cancer Chemother Pharmacol 2006;58(4):532-539
31. Springer JB, Colvin ME, Colvin OM, Ludeman SM. Isophosphoramide mustard and its mechanism of bisalkylation. J Org Chem 1998;63:7218-7222
32. Busse D, Busch FW, Bohnenstengel F, et al. Dose escalation of cyclophosphamide in patients with breast cancer: consequences for pharmacokinetics and metabolism. J Clin Oncol 1997;15:1885-1896 (Pubitemid 27209518)
33. Goren MP, Wright RK, Pratt CB, Pell FE. Dechloroethylation of ifosfamide and neurotoxicity. Lancet 1986;2(8517):1219-1220
34. Ren S, Yang JS, Kalhorn TF, Slattery JT. Oxidation of cyclophosphamide to 4-hydroxycyclophosphamide and deschloroethylcyclophosphamide in human liver microsomes. Cancer Res 1997;57:4229-4235
35. Roy P, Tretyakov O, Wright J, Waxman DJ. Stereoselective metabolism of ifosfamide by human P-450s 3A4 and 2B6. Favorable metabolic properties of R-enantiomer. Drug Metab Dispos 1999b;27(11):1309-1318
36. McCune JS, Risler LJ, Phillips BR, et al. Contribution of CYP3A5 to hepatic and renal ifosfamide N-dechloroethylation. Drug Metab Dispos 2005;33(7):1074-1081
37. Huang Z, Roy P, Waxman DJ. Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamide. Biochem Pharmacol 2000;59(8):961-972
38. Zhang J, Tian Q, Zhou SF. Clinical Pharmacology of Cyclophosphamide and Ifosfamide. Curr Drug Ther 2006;1:55-84
39. DiMaggio JR, Brown R, Baile WF, Schapira D. Hallucinations and ifosfamide-induced neurotoxicity. Cancer 1994;73(5):1509-1514
40. Skinner R, Sharkey IM, Pearson AD, Craft AW. Ifosfamide, mesna, and nephrotoxicity in children. J Clin Oncol 1993;11(1):173-190
41. May-Manke A, Kroemer H, Hempel G, et al. Investigation of the major human hepatic cytochrome P450 involved in 4-hydroxylation and N-dechloroethylation of trofosfamide. Cancer Chemother Pharmacol 1999;44(4):327-334
42. Yu L, Waxman DJ. Role of cytochrome P450 in oxazaphosphorine metabolism. Deactivation via N-dechloroethylation and activation via 4-hydroxylation catalyzed by distinct subsets of rat liver cytochromes P450. Drug Metab Dispos 1996;24(11):1254-1262
43. Holm KA, Kindberg CG, Stobaugh JF, et al. Stereoselective pharmacokinetics and metabolism of the enantiomers of cyclophosphamide. Preliminary results in humans and rabbits. Biochem Pharmacol 1990;39:1375-1384
44. Miranda-Silva C, Fernandes BJ, Donadi EA, et al. Influence of glomerular filtration rate on the pharmacokinetics of cyclophosphamide enantiomers in patients with lupus nephritis. J Clin Pharmacol 2009;49(8):965-972
45. Williams ML, Wainer IW, Embree L, et al. Enantioselective induction of cyclophosphamide metabolism by phenytoin. Chirality 1999a;11:569-574
46. Chang TK, Yu L, Maurel P, Waxman DJ. Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. Cancer Res 1997b;57(10):1946-1954
47. Chen CS, Jounaidi Y, Waxman DJ. Enantioselective metabolism and cytotoxicity of R-ifosfamide and S-ifosfamide by tumor cell-expressed cytochromes P450. Drug Metab Dispos 2005;33(9):1261-1267
48. Corlett SA, Parker D, Chrystyn H. Pharmacokinetics of ifosfamide and its enantiomers following a single 1 h intravenous infusion of the racemate in patients with small cell lung carcinoma. Br J Clin Pharmacol 1995;39:452-455
49. Wainer IW, Ducharme J, Granvil CP. The N-dechloroethylation of ifosfamide: using stereochemistry to obtain an accurate picture of a clinically relevant metabolic pathway. Cancer Chemother Pharmacol 1996;37:332-336
50. Granvil CP, Ducharme J, Leyland-Jones B, et al. Stereoselective pharmacokinetics of ifosfamide and its 2-and 3-N-dechloroethylated metabolites in female cancer patients. Cancer Chemother Pharmacol 1996;37:451-456
51. Granvil CP, Madan A, Sharkawi M, et al. Role of CYP2B6 and CYP3A4 in the in vitro N-dechloroethylation of (R)-and (S)-ifosfamide in human liver microsomes. Drug Metab Dispos 1999;27:533-541
52. Boddy AV, Proctor M, Simmonds D, et al. Pharmacokinetics, metabolism and clinical effect of ifosfamide in breast cancer patients. Eur J Cancer 1995;31A(1):69-76
53. Williams ML, Wainer IW. Cyclophosphamide versus ifosfamide: to use ifosfamide or not to use, that is the three-dimensional question. Curr Pharm Des 1999b;5:665-672
54. Kurowski V, Wagner T. Comparative pharmacokinetics of ifosfamide, 4-hydroxyifosfamide, chloroacetaldehyde, and 2-and 3-dechloroethylifosfamide in patients on fractionated intravenous ifosfamide therapy. Cancer Chemother Pharmacol 1993;33(1):36-42
55. Brüggemann SK, Kisro J, Wagner T. Ifosfamide cytotoxicity on human tumor and renal cells: role of chloroacetaldehyde in comparison to 4-hydroxyifosfamide. Cancer Res 1997;57:2676-2680
56. Spengler SJ, Singer B. Formation of interstrand cross-links in chloroacetaldehyde-treated DNA demonstrated by ethidium bromide fluorescence. Cancer Res 1988;48:4804-4806
57. Sood C, O'Brien PJ. Molecular mechanisms of chloroacetaldehyde-induced cytotoxicity in isolated rat hepatocytes. Biochem Pharmacol 1993;46:1621-1626 (Pubitemid 23338497)
58. Brüggemann SK, Radike K, Braasch K, et al. Chloroacetaldehyde: mode of antitumor action of the ifosfamide metabolite. Cancer Chemother Pharmacol 2006;57(3):349-356
59. Lee FY. Glutathione diminishes the anti-tumour activity of 4-hydroperoxycyclophosphamide by stabilising its spontaneous breakdown to alkylating metabolites. Br J Cancer 1991;63:45-50
60. Dirven HA, Ommen Bv, Bladeren PJv. Involvement of human glutathione S-transferase isoenzymes in the conjugation of cyclophosphamide metabolites with glutathione. Cancer Res 1994a;54:6215-6220
61. Dirven HA, Venekamp JC, Ommen B, Bladeren PJ. The interaction of glutathione with 4-hydroxycyclophosphamide and phosphoramidemustard, studied by 31P nuclear magnetic resonance spectroscopy. Chem Biol Interact 1994b;93:185-196
62. Sladek NE. Human aldehyde dehydrogenases: potential pathological, pharmacological, and toxicological impact. J Biochem Mol Toxicol 2003;17(1):7-23
63. Sladek NE. Aldehyde dehydrogenase-mediated cellular relative insensitivity to the oxazaphosphorines. Curr Pharm Des 1999;5(8):607-625
64. Dockham PA, Sreerama L, Sladek NE. Relative contribution of human erythrocyte aldehyde dehydrogenase to the systemic detoxification of the oxazaphosphorines. Drug Metab Dispos 1997;25(12):1436-1441
65. Sladek NE. Anticancer drugs reactive metabolism and drug interactions. Pergamon Press, Tarrytown, NY; 1994
66. Townsend AJ, Leone-Kabler S, Haynes RL, et al. Selective protection by stably transfected human ALDH3A1 (but not human ALDH1A1) against toxicity of aliphatic aldehydes in V79 cells. Chem Biol Interact 2001;30(130-132):261-273
67. Huang CY, Huang KL, Cheng TJ, et al. The GST T1 and CYP2E1 genotypes are possible factors causing vinyl chloride induced abnormal liver function. Arch Toxicol 1997;71(8):482-488
68. Dubourg L, Michoudet C, Cochat P, Baverel G. Human kidney tubules detoxify chloroacetaldehyde, a presumed nephrotoxic metabolite of ifosfamide. J Am Soc Nephrol 2001;12(8):1615-1623
69. Dubourg L, Taniere P, Cochat P, et al. Toxicity of chloroacetaldehyde is similar in adult and pediatric kidney tubules. Pediatr Nephrol 2002;17(2):97-103
70. Kohn KW, Hartley JA, Mattes WB. Mechanisms of DNA sequence alkylation of guanine-N7 positions by nitrogen mustards. Nucleic Acids Res 1987;14:10531-10545
71. Crook TR, Souhami RL, McLean AEM. Cytotoxicity. DNA cross-linking and single strand breaks induced by activated cyclophosphamide and acrolein in human leukemia cells. Cancer Res 1996;46:5029-5034
72. Hickman JA. Apoptosis and cancer chemotherapy. Cancer Metastasis Rev 1992;11:121-139
73. Schwartz PS, Waxman DJ. Cyclophosphamide induces caspase 9-dependent apoptosis in 9 L tumor cells. Mol Pharmacol 2001;60:1268-1279
74. Karle P, Renner M, Salmons B, Gunzburg WH. Necrotic, rather than apoptotic, cell death caused by cytochrome P450-activated ifosfamide. Cancer Gene Ther 2001;8:220-230
75. Gamcsik MP, Dolan ME, Andersson BS, Murray D. Mechanisms of resistance to the toxicity of cyclophosphamide. Curr Pharm Des 1999;5(8):587-605
76. Buckner CD, Rudolph RH, Fefer A, et al. High dose cyclophosphamide therapy for malignant disease. Cancer (Phila) 1972;29:357-365
77. Berrigan MJ, Marinello AJ, Pavelic Z, et al. Protective role of thiols in cyclophosphamide-induced urotoxicity and depression of hepatic drug metabolism. Cancer Res 1982;42(9):3688-3695
78. Brock N, Stekar J, Pohl J, et al. Acrolein. The causative factor of urotoxic side-effects of cyclophosphamide, ifosphamide, trophosphamide and sufosfamide. Arzneimittelforschung 1979;29:659-661
79. Cox PJ. Cyclophosphamide cystitis-identification of acrolein as the causative agent. Biochem Pharmacol 1979;28(13):2045-2049
80. Broadhead CL, Walker D, Skinner R, Simmons NL. Differential cytotoxicity of ifosfamide and its metabolites in renal epithelial cell cultures. Toxicol in Vitro 1998;12(3):209-217
81. Fontana-Donatelli G, Dambrosio F. Observations on the behaviour of hematic crasis in 134 patients subjected to chemotherapeutic treatment with cyclophosphamide for genital neoplasms. Ann Obstet Gynecol Med Perinat 1963;85:929-940
82. Korkmaz A, Topal T, Oter S. Pathophysiological aspects of cyclophosphamide and ifosfamide induced hemorrhagic cystitis; implication of reactive oxygen and nitrogen species as well as PARP activation. Cell Biol Toxicol 2007;23(5):303-312
83. Stillwell TJ, Benson RCJ, Burgert EOJ. Cyclophosphamide-induced hemorrhagic cystitis in Ewing's sarcoma. J Clin Oncol 1988;6(1):76-82
84. Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med 1996;124(5):477-484
85. Siu LL, Moore MJ. Use of mesna to prevent ifosfamide-induced urotoxicity. Support Care Cancer 1998;6(2):144-154
86. Ormstad K, Orrenius S, Låstbom T, et al. Pharmacokinetics and metabolism of sodium 2-mercaptoethanesulfonate in the rat. Cancer Res 1983;43(1):333-338
87. Mohrmann M, Ansorge S, Sch€onfeld B, Brandis M. Dithio-bis- mercaptoethanesulphonate (DIMESNA) does not prevent cellular damage by metabolites of ifosfamide and cyclophosphamide in LLC-PK1 cells. Pediatr Nephrol 1994;8(4):458-465
88. Mota JM, Brito GA, Loiola RT, et al. Interleukin-11 attenuates ifosfamide-induced hemorrhagic cystitis. Int Braz J Urol 2007;33(5):704-710
89. Batista CK, Mota JM, Souza ML, et al. Amifostine and glutathione prevent ifosfamide-and acrolein-induced hemorrhagic cystitis. Cancer Chemother Pharmacol 2007;59(1):71-77
90. Berrak SG, Pearson M, Berberoǧlu S, et al. High-dose ifosfamide in relapsed pediatric osteosarcoma: therapeutic effects and renal toxicity. Pediatr Blood Cancer 2005;44(3):251-259
91. Prince HM, Gardyn J, Millward MJ, et al. Ifosfamide in combination with paclitaxel or doxorubicin: regimens which effectively mobilize peripheral blood progenitor cells while demonstrating anti-tumor activity in patients with metastatic breast cancer. Bone Marrow Transplant 1999;23(5):427-435
92. Skinner R. Chronic ifosfamide nephrotoxicity in children. Med Pediatr Oncol 2003;41(3):190-197
93. Oberlin O, Fawaz O, Rey A, et al. Long-term evaluation of Ifosfamide-related nephrotoxicity in children. J Clin Oncol 2009;27(32):5350- 5355
94. Jones DP, Chesney RW. Renal toxicity of cancer chemotherapeutic agents in children: ifosfamide and cisplatin. Curr Opin Pediatr 1995;7(2):208-213
95. Fujieda M, Matsunaga A, Hayashi A, et al. Children's toxicology from bench to bed-Drug-induced renal injury (2): Nephrotoxicity induced by cisplatin and ifosfamide in children. J Toxicol Sci 2009;34(Suppl 2):251-257
96. St€ohr W, Paulides M, Bielack S, et al. Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: a report from the Late Effects Surveillance System. Pediatr Blood Cancer 2007;48(4):447-452 (Pubitemid 46340112)
97. Skinner R, Cotterill SJ, Stevens MC. Risk factors for nephrotoxicity after ifosfamide treatment in children: a UKCCSG Late Effects Group study. United Kingdom Children's Cancer Study Group. Br J Cancer 2000;82(10):1636-1645
98. English MW, Skinner R, Pearson AD, et al. The influence of ifosfamide scheduling on acute nephrotoxicity in children. Br J Cancer 1997;75(9):1356-1359
99. Aleksa K, Woodland C, Koren G. Young age and the risk for ifosfamide-induced nephrotoxicity: a critical review of two opposing studies. Pediatr Nephrol 2001;16(12):1153-1158
100. Pratt CB, Green AA, Horowitz ME, et al. Central nervous system toxicity following the treatment of pediatric patients with ifosfamide/mesna. J Clin Oncol 1986;4(8):1253-1261
101. Dufour C, Grill J, Sabouraud P, et al. Ifosfamide induced encephalopathy: 15 observations. Arch Pediatr 2006;13(2):140-145
102. Kerdudo C, Orbach D, Sarradet JL, Doz F. Ifosfamide neurotoxicity: an atypical presentation with psychiatric manifestations. Pediatr Blood Cancer 2006;47(1):100-102
103. Shuper A, Stein J, Goshen J, et al. Subacute central nervous system degeneration in a child: an unusual manifestation of ifosfamide intoxication. J Child Neurol 2000;15(7):481-483
104. Norwood R, Anderson MD, Deepak S, Tandon MD. Ifosfamide extrapyramidal neurotoxicity. Cancer 2001;68(1):72-75
105. Busse D, Busch FW, Schweizer E, et al. Fractionated administration of high-dose cyclophosphamide: influence on dose-dependent changes in pharmacokinetics and metabolism. Cancer Chemother Pharmacol 1999;43(3):263-268
106. Ghosn M, Carde P, Leclerq B, et al. Ifosfamide/mesna related encephalopathy: a case report with a possible role of phenobarbital in enhancing neurotoxicity. Bull Cancer 1988;75(4):391-392
107. Durand JP, Gourmel B, Mir O, Goldwasser F. Antiemetic neurokinin-1 antagonist aprepitant and ifosfamide-induced encephalopathy. Ann Oncol 2007;18(4):808-809
108. Curtin JP, Koonings PP, Gutierrez M, Morrow JBSCP. Ifosfamide-induced neurotoxicity. Gynecol Oncol 1991;42(3):193-196
109. Cerny T, Castiglione M, Brunner K, et al. Ifosfamide by continuous infusion to prevent encephalopathy. Lancet 1990;335(8682):175
110. Kurowski V, Cerny T, Küpfer A, Wagner T. Metabolism and pharmacokinetics of oral and intravenousifosfamide. J Cancer Res Clin Oncol 1991;117(Suppl 4):148-153
111. Lind MJ, Margison JM, Cerny T, et al. Comparative pharmacokinetics and alkylating activity of fractionated intravenous and oral ifosfamide in patients with bronchogenic carcinoma. Cancer Res 1989;49(3):753-757
112. Zamlauski-Tucker MJ, Morris ME, Springate JE. Ifosfamide metabolite chloroacetaldehyde causes Fanconi syndrome in the perfused rat kidney. Toxicol Appl Pharmacol 1994;129(1):170-175
113. Mohrmann M, Pauli A, Ritzer M, et al. Inhibition of sodium-dependent transport systems in LLC-PK1 cells by metabolites of ifosfamide. Ren Physiol Biochem 1992;15(6):289-301
114. Mohrmann M, Küpper N, Sch€onfield B, Brandis M. Ifosfamide and mesna: effects on the Na/H exchanger activity in renal epithelial cells in culture (LLC-PK1). Ren Physiol Biochem 1995;18(3):118-127
115. Yaseen Z, Michoudet C, Baverel G, Dubourg L. In vivo mesna and amifostine do not prevent chloroacetaldehyde nephrotoxicity in vitro. Pediatr Nephrol 2008;23(4):611-618
116. Springate J, Chan K, Lu H, et al. Toxicity of ifosfamide and its metabolite chloroacetaldehyde in cultured renal tubule cells. In Vitro Cell Dev Biol Anim 1999;35(6):314-317
117. Sood C, O'Brien PJ. 2-Chloroacetaldehyde-induced cerebral glutathione depletion and neurotoxicity. Br J Cancer Suppl 1996;27:S287-93
118. Springate J, Taub M. Ifosfamide toxicity in cultured proximal renal tubule cells. Pediatr Nephrol 2007;22(3):358-365
119. Aleksa K, Halachmi N, Ito S, Koren G. A tubule cell model for ifosfamide nephrotoxicity. Can J Physiol Pharmacol 2005;83(6):499-508
120. Knouzy B, Dubourg L, Baverel G, Michoudet C. Targets of chloroacetaldehyde-induced nephrotoxicity. Toxicol In Vitro 2010;24(1):99-107
121. Visarius TM, Stucki JW, Lauterburg BH. Inhibition and stimulation of long-chain fatty acid oxidation by chloroacetaldehyde and methylene blue in rats. J Pharmacol Exp Ther 1999;289(2):820-824
122. DiCataldo A, Astuto M, Rizzo G, et al. Neurotoxicity during ifosfamide treatment in children. Med Sci Monit 2009;15(1):CS22-5
123. Küpfer A, Aeschlimann C, Cerny T. Methylene blue and the neurotoxic mechanisms of Ifosfamide encephalopathy. Eur J Clin Pharmacol 1996;50(4):249-252
124. Chatton JY, Idle JR, Vågbø CB, Magistretti PJ. Insights into the mechanisms of ifosfamide encephalopathy: drug metabolites have agonistic effects on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors and induce cellular acidification in mouse cortical neurons. J Pharmacol Exp Ther 2001;299(3):1161-1168
125. Gonzalez-Angulo AM, Orzano JA, Davila E. Ifosfamide-induced encephalopathy. South Med J 2002;95(10):1215-1217
126. Cerny T, Küpfer A. The enigma of ifosfamide encephalopathy. Ann Oncol 1992;3(9):679-681
127. Zaki EL, Springate JE, Taub M. Comparative toxicity of ifosfamide metabolites and protective effect of mesna and amifostine in cultured renal tubule cells. Toxicol In Vitro 2003;17(4):397-402
128. Brock N, Pohl J. Prevention of urotoxic side effects by regional detoxification with increased selectivity of oxazaphosphorine cytostatics. IARC Sci Publ 1986;78:269-279
129. Schwerdt G, Gordjani N, Benesic A, et al. Chloroacetaldehyde-and acrolein-induced death of human proximal tubule cells. Pediatr Nephrol 2006;21(1):60-67
130. Chen N, Aleksa K, Woodland C, et al. N-Acetylcysteine prevents ifosfamide-induced nephrotoxicity in rats. Br J Pharmacol 2008;153(7):1364-1372
131. Ferrero JM, Eftekari P, Largillier R, et al. [Treatment of ifosfamide induced encephalopathy with methylene-blue]. Bull Cancer 1995;82(7):598-599
132. Küpfer A, Aeschlimann C, Wermuth B, Cerny T. Prophylaxis and reversal of ifosfamide encephalopathy with methylene-blue. Lancet 1994;343(8900):763-764
133. Frisk P, Stålberg E, Str€omberg B, Jakobson A. Painful peripheral neuropathy after treatment with high-dose ifosfamide. Med Pediatr Oncol 2001;37(4):379-382
134. Pelgrims J, Vos FD, Van den Brande J, et al. Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature. Br J Cancer 2000;82:291-294
135. Aeschlimann C, Küpfer A, Schefer H, Cerny T. Comparative pharmacokinetics of oral and intravenous ifosfamide/ mesna/methylene blue therapy. Drug Metab Dispos 1998;26(9):883-890
136. Patel PN. Methylene blue for management of Ifosfamide-induced encephalopathy. Ann Pharmacother 2006;40(2):299-303
137. Buesa JM, García-Teijido P, Losa R, Fra J. Treatment of ifosfamide encephalopathy with intravenous thiamine. Clin Cancer Res 2003;9(12):4636-4637
138. Hamadani M, Awan F. Role of thiamine in managing ifosfamide-induced encephalopathy. J Oncol Pharm. Pract 2006;12:237-239
139. Kasper B, Harter C, Meissner J, et al. Prophylactic treatment of known ifosfamide-induced encephalopathy for chemotherapy with high-dose ifosfamide? Support Care Cancer 2004;12(3):205-207
140. Brain EG, Yu LJ, Gustafsson K, et al. Modulation of P450-dependent ifosfamide pharmacokinetics: a better understanding of drug activation in vivo. Br J Cancer 1998;77:1768-1776
141. Yu LJ, Drewes P, Gustafsson K, et al. In vivo modulation of alternative pathways of P-450-catalyzed cyclophosphamide metabolism: impact on pharmacokinetics and antitumor activity. J Pharmacol Exp Ther 1999;288:928-937
142. Wei MX, Tamiya T, Chase M, et al. Experimental tumor therapy in mice using the cyclophosphamide-activating cytochrome P450 2B1 gene. Hum Gene Ther 1994;5:969-978
143. Philpott GW, Shearer W, Bower RJ, Parker CW. Selective cytotoxicity of hapten-substituted cells with an antibody-enzyme conjugate. J Immunol 1973;111(3):921-929
144. Fang L, Sun D. Predictive physiologically based pharmacokinetic model for antibody-directed enzyme prodrug therapy. Drug Metab Dispos 2008;36(6):1153-1165
145. Kan O, Griffiths L, Baban D, et al. Direct retroviral delivery of human cytochrome P450 2B6 for gene-directed enzyme prodrug therapy of cancer. Cancer Gene Ther 2001;8:473-482
146. Kan O, Kingsman S, Naylor S. Cytochrome P450-based cancer gene therapy: current status. Expert Opin Biol Ther 2002;2:857-868
147. Braybrooke JP, Slade A, Deplanque G, et al. Phase I study of MetXia-P450 gene therapy and oral cyclophosphamide for patients with advanced breast cancer or melanoma. Clin Cancer Res 2005;11:1512-1520
148. Chen L, Waxman DJ. Intratumoral activation and enhanced chemotherapeutic effect of oxazaphosphorines following cytochrome P-450 gene transfer: development of a combined chemotherapy/cancer gene therapy strategy. Cancer Res 1995;55(3):581-589
149. Samuel S, Keese M, Lux A, et al. Peritoneal cancer treatment with CYP2B1 transfected, microencapsulated cells and ifosfamide. Cancer Gene Ther 2006;13(1):65-73
150. Rooseboom M, Commandeur JN, Vermeulen NP. Enzyme catalyzed activation of anticancer prodrugs. Pharmacol Rev 2004;56:53-102
151. Roy P, Waxman DJ. Activation of oxazaphosphorines by cytochrome P450: application to gene-directed enzyme prodrug therapy for cancer. Toxicol In Vitro 2006;20(2):176-186
152. Connors TA, Cox PJ, Farmer PB, et al. Some studies of the active intermediates formed in the microsomal metabolism of cyclophosphamide and iphosphamide. Biochem Pharmacol 1974;23:115-129
153. Reske SN, Grillenberger KG, Glatting G, et al. Overexpression of glucose transporter 1 and increased FDG uptake in pancreatic carcinoma. J Nucl Med 1997;38:1344-1348
154. Seker H, Bertram B, Wieber M. Possible role of the cytosolic b-glucosidase in the metabolism of saccharide-coupled platinum and ifosfamide mustard in tumor cells. Monduzzi, Milan, 1996
155. Pohl J, Bertram B, Hilgard P, et al. D-19575-a sugar-linked isophosphoramide mustard derivative exploiting transmembrane glucose transport. Cancer Chemother Pharmacol 1995;35:364-370
156. Pohl J, Hilgard P, Jahn W, Zechel HJ. Experimental toxicology of ASTA Z 7557 (INN mafosfamide). Invest New Drugs 1984;2(2):201-206
157. Pette M, Gold R, Pette DF, et al. Mafosfamide induces DNA fragmentation and apoptosis in human Tlymphocytes. A possible mechanism of its immunosuppressive action. Immunopharmacology 1995;30:59-69
158. Voelcker G, Bielicki L, Hohorst HJ. Thiazolidinyl-and perhydrothiazinylphosphamidesters: toxicity and preliminary antitumour evaluation. J Cancer Res Clin Oncol 1997;123(11-12):623-631
159. Paci A, Guillaume D, Husson HP. Synthesis of side-chain substituted ifosfamide analogs. J Heterocyclic Chem 2001b;38:1131-1134
160. Storme T, Deroussent A, Mercier L, et al. New ifosfamide analogs designed for lower associated neurotoxicity and nephrotoxicity with modified alkylating kinetics leading to enhanced in vitro anticancer activity. J Pharmacol Exp Ther 2009;328:598-609