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Systematic (IUPAC) name
(RS)-N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide
Clinical data
Trade names Lyophilizedcytoxan
AHFS/ monograph
MedlinePlus a682080
Pregnancy cat. D (AU) D (US)
Legal status Prescription only
Routes Oral, intravenous
Pharmacokinetic data
Bioavailability >75% (oral)
Protein binding >60%
Metabolism Hepatic
Half-life 3-12 hours
Excretion Renal
CAS number 50-18-0 YesY
ATC code L01AA01
DrugBank DB00531
ChemSpider 2804 YesY
UNII 6UXW23996M YesY
KEGG D07760 YesY
Chemical data
Formula C7H15Cl2N2O2P 
Mol. mass 261.086 g/mol
Physical data
Melt. point 2 °C (36 °F)
 YesY (what is this?)  (verify)

Cyclophosphamide (INN, trade names Endoxan, Cytoxan, Neosar, Procytox, Revimmune), also known as cytophosphane,[1] is a nitrogen mustard alkylating agent[2] from the oxazaphosphinans group.

An alkylating agent adds an alkyl group (CnH2n+1) to DNA. It attaches the alkyl group to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring. This interferes with DNA replication by forming intrastrand and interstrand DNA crosslinks.

Cyclophosphamide is used to treat cancers and autoimmune disorders. As a prodrug, it is converted by liver cytochrome P450 (CYP) enzymes to form the metabolite 4-hydroxy cyclophosphamide that have chemotherapeutic activity.[3]

Cyclophosphamide has severe and life-threatening adverse effects, including acute myeloid leukemia, bladder cancer, hemorrhagic cystitis, and permanent infertility, especially at higher doses. For autoimmune diseases, doctors often substitute less-toxic methotrexate or azathioprine after an acute crisis.[4]


Cyclophosphamide is used for the treatment of numerous malignant processes and certain autoimmune diseases. Goals of therapy are prompt control of the underlying pathological process and discontinuation or replacement of cyclophosphamide with less toxic, alternative medication as soon as possible in order to minimize associated morbidity. Regular and frequent laboratory evaluations are required to monitor renal function, avoid drug-induced bladder complications, and screen for bone marrow toxicity.

Like other alkylating agents, cyclophosphamide is teratogenic and contraindicated in pregnant women (Pregnancy Category D) except for life-threatening circumstances in the mother.[5][6] Additional relative contraindications to the use of cyclophosphamide include lactation, active infection, neutropenia, or bladder toxicity.


Cyclophosphamide IV drip

The main use of cyclophosphamide is with other chemotherapy agents in the treatment of lymphomas, some forms of brain cancer, leukemia[7] and some solid tumors.[8] It is a chemotherapy drug that works by inducing the death of certain T cells.

A 2004 study[9] showed the biological actions of cyclophosphamide are dose-dependent. At higher doses, it is associated with increased cytotoxicity and immunosuppression, while at low, continuous doses, it shows immunostimulatory and antiangiogenic properties. A 2009 study of 17 patients with docetaxel-resistant metastatic hormone refractory prostate cancer showed a prostate-specific antigen (PSA) decrease in 9 of the 17 patients. Median survival was 24 months for the entire group, and 60 months for those with a PSA response. The study concluded low-dose cyclophosphamide "might be a viable alternative" treatment for docetaxel-resistant MHRPC and "is an interesting candidate for combination therapies, e.g., immunotherapy, tyrosine kinase inhibitors, and antiangiogenisis."[10]

Autoimmune diseases[edit]

Cyclophosphamide decreases the immune system's response, and although concerns about toxicity restrict its use to patients with severe disease, it remains an important treatment for life-threatening manifestations of autoimmune diseases where disease-modifying antirheumatic drugs (DMARDs) have been ineffective. For example, systemic lupus erythematosus with severe lupus nephritis[11] may respond to pulsed cyclophosphamide. Cyclophosphamide is also used to treat minimal change disease,[12] severe rheumatoid arthritis,[13] Wegener's granulomatosis[14] (with trade name Cytoxan), and multiple sclerosis[15] (with trade name Revimmune).


Oral cyclophosphamide is rapidly absorbed and then converted by mixed-function oxidase enzymes (cytochrome P450 system) in the liver to active metabolites.[16] The main active metabolite is 4-hydroxycyclophosphamide, which exists in equilibrium with its tautomer, aldophosphamide. Most of the aldophosphamide is then oxidised by the enzyme aldehyde dehydrogenase (ALDH) to make carboxycyclophosphamide. A small proportion of aldophosphamide freely diffuses into cells, where it is decomposed into two compounds, phosphoramide mustard and acrolein.[17] The active metabolites of cyclophosphamide are highly protein bound and distributed to all tissues, are assumed to cross the placenta and are known to be present in breast milk.[18]

Cyclophosphamide metabolites are primarily excreted in the urine unchanged, and drug dosing should be appropriate adjusted in the setting of renal dysfunction.[19] Drugs altering hepatic microsomal enzyme activity (e.g., alcohol, barbiturates, rifampin, or phenytoin) may result in accelerated metabolism of cyclophosphamide into its active metabolites, increasing both pharmacologic and toxic effects of the drug; alternatively, drugs that inhibit hepatic microsomal enzymes (e.g. corticosteroids, tricyclic antidepressants, or allopurinol) result in slower conversion of cyclophosphamide into its metabolites and consequently reduced therapeutic and toxic effects.[20]

Cyclophosphamide reduces plasma pseudocholinesterase activity and may result in prolonged neuromuscular blockade when administered concurrently with succinylcholine.[21][22] Tricyclic antidepressants and other anticholinergic agents can result in delayed bladder emptying and prolonged bladder exposure to acrolein.

Mechanism of action[edit]

The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard. This metabolite is only formed in cells that have low levels of ALDH. Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at guanine N-7 positions (known as interstrand and intrastrand crosslinkages, respectively). This is irreversible and leads to cell apoptosis.[23]

Cyclophosphamide has relatively little typical chemotherapy toxicity as ALDHs are present in relatively large concentrations in bone marrow stem cells, liver and intestinal epithelium. ALDHs protect these actively proliferating tissues against toxic effects of phosphoramide mustard and acrolein by converting aldophosphamide to carboxyphosphamide that does not give rise to the toxic metabolites phosphoramide mustard and acrolein.

Cyclophosphamide induces beneficial immunomodulatory effects in adaptive immunotherapy. Suggested mechanisms include:[24]

  1. Elimination of T regulatory cells (CD4+CD25+ T cells) in naive and tumor-bearing hosts
  2. Induction of T cell growth factors, such as type I IFNs, and/or
  3. Enhanced grafting of adoptively transferred, tumor-reactive effector T cells by the creation of an immunologic space niche.

Thus, cyclophosphamide preconditioning of recipient hosts (for donor T cells) has been used to enhance immunity in naïve hosts, and to enhance adoptive T cell immunotherapy regimens, as well as active vaccination strategies, inducing objective antitumor immunity.

Side effects[edit]

Adverse drug reactions from cyclophosphamide are related to the cumulative medication dose and include chemotherapy-induced nausea and vomiting,[25] bone marrow suppression,[26] stomach ache, hemorrhagic cystitis, diarrhea, darkening of the skin/nails, alopecia (hair loss) or thinning of hair, changes in color and texture of the hair, and lethargy. Other side effects may include easy bruising/bleeding, joint pain, mouth sores, slow-healing existing wounds, unusual decrease in the amount of urine, or unusual tiredness or weakness.

Cyclophosphamide is itself carcinogenic and may increase the risk of developing lymphomas, leukemia, skin cancer, transitional cell carcinoma of the bladder or other malignancies.[27] Myeloproliferative neoplasms, including acute leukemia, non-Hodgkin lymphoma, and multiple myeloma, occurred in 5 of 119 rheumatoid arthritis patients within the first decade after receiving cyclophosphamide, compared with one case of chronic lymphocytic leukemia in 119 rheumatoid arthritis patients without a history of cyclophosphamide use.[28] Secondary acute myeloid leukemia (therapy-related AML, or "t-AML") is thought to occur either by cyclophosphamide inducing mutations or selecting for a high-risk myeloid clone.[29] This risk may be dependent on dose and a number of other factors, including the condition being treated, other agents or treatment modalities used (including radiotherapy), treatment intensity and length of treatment. For some regimens, it is a very rare occurrence. For instance, CMF-therapy for breast cancer (where the cumulative dose is typically less than 20 grams of cyclophosphamide) seems to carry an AML risk of less than 1/2000th, with some studies even finding no increased risk compared to the background population. Other treatment regimens involving higher doses may carry risks of 1-2% or higher, depending on regimen. Cyclophosphamide-induced AML, when it happens, typically presents some years after treatment, with incidence peaking around 3–9 years. After nine years, the risk has fallen to the level of the regular population. When AML occurs, it is often preceded by a myelodysplastic syndrome phase, before developing into overt acute leukemia. Cyclophosphamide-induced leukemia will often involve complex cytogenetics, which carries a worse prognosis than de novo AML.

Acrolein is toxic to the bladder epithelium and can lead to hemorrhagic cystitis, which is associated with microscopic or gross hematuria and occasionally dysuria.[30] Risks of hemorrhagic cystitis can be minimized with adequate fluid intake, avoidance of nighttime dosage, and mesna (sodium 2-mercaptoethane sulfonate), a sulfhydryl donor which binds and detoxifies acrolein.[31][32] Intermittent dosing of cyclophosphamide decreases cumulative drug dose, reduces bladder exposure to acrolein, and has equal efficacy to daily treatment in the management of lupus nephritis.[33]

Cyclophosphamide has also been found to significantly increase the risk of premature menopause in females and of infertility in males and females alike, the likelihood of which increases with cumulative drug dose and increasing patient age. Such infertility is usually temporary but can rarely be permanent.[34] The use of leuprolide in women of reproductive age before administration of intermittently-dosed cyclophosphamide may diminish the risks of premature menopause and infertility.[35]

Cyclophosphamide is a Pregnancy Category D drug and has been shown to cause birth defects. First trimester exposure to cyclophosphamide for the treatment of cancer or lupus has shown a pattern of anomalies labeled "cyclophosphamide embryopathy," including growth restriction, ear and facial abnormalities, absence of digits, and hypoplastic limbs.[36][37] Women previously treated with alkylating agents are often able to conceive and deliver health children.[38][39]

Neutropenia or lymphoma arising secondary to cyclophosphamide usage can predispose patients to a variety of bacterial, fungal and opportunistic infections.[40] There are no published guidelines for PCP prophylaxis for patients with rheumatological diseases receiving immunosuppressive drugs, but some advocate its use when receiving high-dose medication.[41][42]

Pulmonary injury appears rare,[43] but can present with two distinct clinical patterns: an early, acute pneumonitis and a chronic, progressive fibrosis.[44] Cardiotoxicity is a major problem with oncology patients treated with higher dose regimens.[45]

High-dose intravenous cyclophosphamide can also cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and a potentially fatal hyponatremia when compounded by the intravenous fluids administered to prevent drug-induced cystitis.[46] While SIADH has been described primarily with higher doses of cyclophosphamide, it can also occur with the lower doses used in the management of inflammatory disorders.[47]


As reported by O.M. Colvin in his study of the development of cyclophosphamide and its clinical applications,

Phosphoramide mustard, one of the principle toxic metabolites of cyclophosphamide, was synthesized and reported by Friedman and Seligman in 1954[48] ...It was postulated that the presence of the phosphate bond to the nitrogen atom could inactivate the nitrogen mustard moiety, but the phosphate bond would be cleaved in gastric cancers and other tumors which had a high phosphamidase content. However, in studies carried out after the clinical efficacy of cyclophosphamide was demonstrated, phosphoramide mustard proved to be cytotoxic in vitro (footnote omitted), but to have a low therapeutic index in vivo.[49]

Cyclophosphamide and the related nitrogen mustard-derived alkylating agent ifosfamide were developed by Norbert Brock and ASTA (now Baxter Oncology). Brock and his team synthesised and screened more than 1,000 candidate oxazaphosphorine compounds.[50] They converted the base nitrogen mustard into a nontoxic "transport form". This transport form was a prodrug, subsequently actively transported into the cancer cells. Once in the cells, the prodrug was enzymatically converted into the active, toxic form. The first clinical trials were published at the end of the 1950s.[51][52][53] In 1959 it became the eighth cytotoxic anticancer agent to be approved by the FDA.[30]


  1. ^ National Cancer Dictionary: cyclophosphamide
  2. ^ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
  3. ^ Huttunen et al. (2011) Prodrugs—from Serendipity to Rational Design. Pharmacol Rev 63:750–771
  4. ^ Kasper, Dennis L; Braunwald, Eugene; Fauci, Anthony; et al. (2005). Harrison's Principles of Internal Medicine, 16th ed. New York: McGraw-Hill. p. 2066. ISBN 978-0-07-139140-5. 
  5. ^ Kirshon, B; Wassertrum N, Willis R, et al. (1988). "Teratogenic effects of first-trimester cyclophosphamide therapy". Obstet Gynecol. 72(3 Pt 2): 462–4. PMID 3136412. 
  6. ^ Clowse, ME; Magder L, Petri M (2005). "Cyclophosphamide for lupus during pregnancy". Lupus 14 (8): 593–7. PMID 16175930. 
  7. ^ Shanafelt TD, Lin T, Geyer SM, et al. (June 2007). "Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia". Cancer 109 (11): 2291–8. doi:10.1002/cncr.22662. PMID 17514743. 
  8. ^ Young SD, Whissell M, Noble JC, et al. (2006). "Phase II clinical trial results involving treatment with low-dose daily oral cyclophosphamide, weekly vinblastine, and rofecoxib in patients with advanced solid tumors and". Clinical Cancer Research 12 (10): 3092–8. doi:10.1158/1078-0432.CCR-05-2255. PMID 16707607. 
  9. ^ Nicolini A, Mancini P, Ferrari P, et al (2004). "Oral dose cyclophosphamide in metastatic hormone refractory prostate cancer (MHRPC)". Biomed Parmacother. 58 (8): 447–50. doi:10.1016/j.biopha.2004.08.006. PMID 15464874. 
  10. ^ Nelius T, Klatte T, et al (April 2009). "Clinical outcome of patients with docetaxel-resistant hormone-refractory prostate cancer treated with second-line cyclophosphamide-based metronomic chemotherapy" (PDF). Medical Oncology 27 (2): 363–7. doi:10.1007/s12032-009-9218-8. PMID 19365737. 
  11. ^ Steinberg AD, Kaltreider HB, Staples PJ, et al. (August 1971). "Cyclophosphamide in lupus nephritis: a controlled trial". Annals of Internal Medicine 75 (2): 165–71. PMID 4104337. 
  12. ^ Brenner and Rector's The Kidney: Volume 8
  13. ^ Townes AS, Sowa JM, Shulman LE (May–June 1976). "Controlled trial of cyclophosphamide in rheumatoid arthritis". Arthritis & Rheumatism 19 (3): 563–73. doi:10.1002/art.1780190308. PMID 779796. 
  14. ^ Novack SN, Pearson CM. (April 1971). "Cyclophosphamide therapy in Wegener's granulomatosis". New England Journal of Medicine 284 (17): 938–42. doi:10.1056/NEJM197104292841703. PMID 5551803. 
  15. ^ Makhani N, Gorman MP, Branson HM, et al. (June 2009). "Cyclophosphamide therapy in pediatric multiple sclerosis". Neurology 72 (24): 2076–82. doi:10.1212/WNL.0b013e3181a8164c. PMC 2923592. PMID 19439723. 
  16. ^ Cohen JL, Jao JY (1970). "Enzymatic basis of cyclophosphamide activation by hepatic microsomes of the rat". Journal of Pharmacology and Experimental Therapeutics 174 (2): 206–10. PMID 4393764. 
  17. ^ Boddy AV, Yule SM (2000). "Metabolism and pharmacokinetics of oxazaphosphorines.". Clin Pharmacokinet 38 (4): 291–304. doi:10.2165/00003088-200038040-00001. PMID 10803453. 
  18. ^ Wiernik, PH; Duncan JH (1971). "Cyclophosphamide in human milk". Lancet 1 (7705): 912. PMID 4102054. 
  19. ^ Haubitz, M; Bohnenstengel F, Brunkhorst R, et al. (2002). "Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency". Kidney Int 61 (4): 1495–501. PMID 11918757. 
  20. ^ Donelli, MG; Guaitani A, et al. (1976). "Importance of pharmacokinetic studies on cyclophosphamide (NSC-26271) in understanding its cytotoxic effect". Cancer Treat Rep 60 (4): 395–401. PMID 1277213. 
  21. ^ Koseoglu, V; Chiang J, Chan KW (1999). "Acquired pseudocholinesterase deficiency after high-dose cyclophosphamide". Bone Marrow Transplant 24 (12): 1367–8. PMID 10627651. 
  22. ^ Vigouroux, D; Voltaire L (1995). "Prolonged neuromuscular block induced by mivacurium in a patient treated with cyclophosphamide". Ann Fr Anesth Reanim 14 (6): 508–10. PMID 8745976. 
  23. ^ Hall, AG; Tilby MJ (1992). "Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies". Blood Rev 6 (3): 163–73. PMID 1422285. 
  24. ^ Sigitsu, A; Viaud S, Chaput N, Bracci L, Proietti E, et al. (2011). "Immunomodulatory effects of cyclophosphamide and implementations for vaccine design". Semin Immunopathol 33 (4): 369–383. PMID 21611872. 
  25. ^ Singh, G; Fries JF, Williams CA, et al. (1991). "Toxicity profiles of disease modifying antirheumatic drugs in rheumatoid arthritis". J Rheumatol 18 (2): 188–94. PMID 1673721. 
  26. ^ Lohrmann, HP (1984). "The problem of permanent bone marrow damage after cytotoxic drug treatment". Oncology 41 (3): 180–4. PMID 6374556. 
  27. ^ Bernatsky, S; Clarke AE, Suissa S (2008). "Hematologic malignant neoplasms after drug exposure in rheumatoid arthritis". Arch Intern Med 168 (4): 378–81. doi:10.1001/archinternmed.2007.107. PMID 18299492. 
  28. ^ Radis, CD; Kahl LE, Baker GL, et al. (1995). "Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis. A 20-year followup study". Arthritis Rheum 38 (8): 1120–7. PMID 7639809. 
  29. ^
  30. ^ a b Emadi A, Jones RJ, Brodsky RA (2009). "Cyclophosphamide and cancer: golden anniversary.". Nat Rev Clin Oncol 6 (11): 638–47. doi:10.1038/nrclinonc.2009.146. PMID 19786984. 
  31. ^ Talar-Williams, C; Hijazi YM, Walther MM, et al. (1996). "Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis". Ann Intern Med 124 (5): 477–84. PMID 8602705. 
  32. ^ Monarch, PA; Arnold LM, Merkel PA (2010). "Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseases: a data-driven review". Arthritis Rheum 62 (1): 9–21. doi:10.1002/art.25061. PMID 20039416. 
  33. ^ Boumpas, DT; Austin HA 3rd, Vaughn EM, et al. (1992). "Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis". Lancet 304 (8822): 741–5. PMID 1356175. 
  34. ^ Balow, JE; Austin HA 3rd, Tsokos GC, et al. (1987). "HIN conference. Lupus nephritis". Ann Intern Med 106 (1): 79–94. PMID 3789582. 
  35. ^ Periti, P; Mazzei T, Mini E (2002). "Clinical pharmacokinetics of depot leuprorelin". Clin Pharmacokinet 41 (7): 485–504. PMID 12083977. 
  36. ^ Enns, GM; Roeder E, Chan RT, et al. (1999). "Apparent cyclophosphamide (cytotan) embyyopathy: a distinct phenotype?". Am J Med Genet 86 (3): 237–41. PMID 10482872. 
  37. ^ Vaux, KK; Kahole NC, Jones KL (2003). "Cyclophosphamide, methotrexate, and cytarabine embryopathy: is apoptosis the common pathway?". Birth Defects Res A Clin Mol Teratol 67 (6): 403–8. PMID 12962283. 
  38. ^ Huong, DL; Amoura Z, Duhaut P, et al. (2002). "Risk of ovarian failure and fertility after intravenous cyclophosphamide. A study in 84 patients.". J Rheumatol 29 (12): 2571–6. PMID 12465154. 
  39. ^ Ramsey-Goldman, R; Mientus JM, Kutzer JE, et al. (1993). "Pregnancy outcome in women with systemic lupus erythematosus treated with immunosuppressive drugs". J Rheumatol 20 (7): 1152–7. PMID 8371208. 
  40. ^ Pryor, BD; Bologna SG, Kahl LE (1996). "Risk factors for serious infection during treatment with cyclophosphamide and high-dose corticosteroids for systemic lupus erythematosus". Arthritis Rheum 39 (9): 1475–82. PMID 8814058. 
  41. ^ Ognibene, FP; Shalhamer JH, Hoffman GS, et al. (1995). "Pneumocystis carinii pneumonia: a major complication of immunosuppressive therapy in patients with Wegener's granulomatosis". Am J Respir Crit Care Med 151 (3 Pt 1): 795–9. PMID 7881673. 
  42. ^ Suryaprasad, A; Stone JH (2008). "When is it safe to stop Pneumocystis jiroveci pneumonia prophylaxis? Insights from three cases complicating autoimmune diseases". Arthritis Rheum 59 (7): 1034–9. doi:10.1002/art.23822. PMID 18576286. 
  43. ^ Twohig, KJ; Matthay RA (1990). "Pulmonary effects of cytotoxic agents other than bleomycin". Clin Chest Med 11 (1): 31–54. PMID 1691069. 
  44. ^ Malik, SW; Myers JL, DeRemee RA, Specks U (1996). "Lung toxicity associated with cyclophosphamide use. Two distinct patterns". Am J Respir Crit Care Med 154 (6 Pt 1): 1851–6. PMID 8970380. 
  45. ^ Floyd, JD; Nguyen DT, Lobins RL, et al. (2005). "Cardiotoxicity of Cancer Therapy". J Clin Oncol 23 (30): 7685–96. PMID 16234530. 
  46. ^ Bressler, RB; Huston DP (1985). "Water intoxication following moderate-dose intravenous cyclophosphamide". Arch Intern Med 145 (3): 548–9. PMID 3977522. 
  47. ^ Salido, M; Macarron P, Hernández-García C, et al. (2003). "Water intoxication induced by low-dose cyclophosphamide in two patients with systemic lupus erythematosus". Lupus 12 (8): 636–9. PMID 12945725. 
  48. ^ O.M. Friedman and A.M. Seligman (1954), J. Amer. Chem. Soc. 76, 655
  49. ^ O.M. Colvin (August 1999), "An Overview of Cyclophosphamide's Development and Clinical Applications", Current Pharmaceutical Design, 5(8):555–60. Colvin, O. M. (1999). "An overview of cyclophosphamide development and clinical applications". Current pharmaceutical design 5 (8): 555–560. PMID 10469891.  edit.
  50. ^ Brock N (1996). "The history of the oxazaphosphorine cytostatics". Cancer 78 (3): 542–7. doi:10.1002/(SICI)1097-0142(19960801)78:3<542::AID-CNCR23>3.0.CO;2-Y. PMID 8697402. 
  51. ^ Wilmanns, H. (1958). Asta-Forschung und Therapie. 
  52. ^ Gross, R., and Wulf, G. (1959). "Klinische und experimentelle Erfahrungen mit zyk lischen und nichtzyklischen Phosphamidestern des N-Losl in der Chemotherapie von Tumoren". Strahlentherapie. 41 (Sonderband III): 361–367. 
  53. ^ Brock N (1989). "Oxazaphosphorine cytostatics: past-present-future. Seventh Cain Memorial Award lecture" (PDF). Cancer Res. 49 (1): 1–7. PMID 2491747. 

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