Cyclophosphamide

In summary, highly reactive metabolites of Cy disrupt DNA synthesis, thus inhibiting cell proliferation. As a result, production of lymphocytes and accessory cells is suppressed, and host immunocompetence is compromised. As noted below and summarized in Table 32.5, for a number of immunosuppressive compounds a metabolic product rather than the parent compound is responsible for the toxicity. 

TABLE 32.5. Examples of Ininiuiiotoxic Compounds Requiring Metabolic Activation 

3- Methylcholanthrene Chlordane Malathion Parathion Cyclophosphamide Dimethylnitrosamine 

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Antineoplastic Drugs. Cyclophosphamide (193) produces antineoplastic effects (see Chemotherapeutics, anticancer) via biochemical conversion to a highly reactive phosphoramide mustard (194) it is chiral owing to the tetrahedral phosphoms atom. The therapeutic index of the (3)-(-)-cyclophosphamide [50-18-0] (193) is twice that of the (+)-enantiomer due to increased antitumor activity the enantiomers are equally toxic (139). The effectiveness of the DNA intercalator dmgs adriamycin [57-22-7] (195) and daunomycin [20830-81-3] (196) is affected by changes in stereochemistry within the aglycon portions of these compounds. Inversion of the carbohydrate C-1 stereocenter provides compounds without activity. The carbohydrate C-4 epimer of adriamycin, epimbicin [56420-45-2] is as potent as its parent molecule, but is significandy less toxic (139). 

Chemotherapeutic agents are grouped by cytotoxic mechanism. The alkylating agents, such as cyclophosphamide [50-18-0] and melphalan [148-82-3] interfere with normal cellular activity by alkylation deoxyribonucleic acid (DNA). Antimetabohtes, interfering with complex metaboHc pathways in the cell, include methotrexate [59-05-2] 5-fluorouracil [51-21-8] and cytosine arabinoside hydrochloride [69-74-9]. Antibiotics such as bleomycin [11056-06-7] and doxombicin [23214-92-8] h.a.ve been used, as have the plant alkaloids vincristine [57-22-7] and vinblastine [865-21-4]. 

Cyclopent-2-en-l-one, 2-hydroxy-3-methyl-synthesis, 3, 693 Cyclopentenone, 4-methoxy-formation, 1, 423 Cyclopenthiazide as diuretic, 1, 174 Cyclopent[2,3-d]isoxazol-4-one structure, 6, 975 Cyclophane conformation, 2, 115 photoelectron spectroscopy, 2, 140 [2,2]Cyclophane conformation, 2, 115 Cyclophanes nomenclature, 1, 27 Cyclophosphamide as pharmaceutical, 1, 157 reviews, 1, 496 Cyclopiloselloidin synthesis, 3, 743 Cyclopolymerization heterocycle-forming, 1, 292-293 6H-Cyclopropa[5a,6a]pyrazolo[l,5-a]pyrimidine pyrazoles from, 5, 285 Cydopropabenzopyran synthesis, 3, 700 Cyclopropachromenes synthesis, 3, 671 Cyclopropa[c]dnnolines synthesis, 7, 597 Cyclopropanation by carbenes... 

Cycle pent hi azide 1, 368 Cyclophosphamide 3, 161 Cycl opryazate 1, 5 2 Cycloserine 14 Cyclothiazide 358 Cycrimine U 47 Cyheptamide 222 Cypenamine 2, 7 Cyprazepam 7, 402 Cyproheptadine 161... 

D. Masurel and F W. Wainer, Analytical and preparative high-performance liquid cliromatographic separation of the enantiomers of ifosfamide, cyclophosphamide and ti ofosfamide and their determination in plasma , 7. Chromatogr. 490 133-143 (1989). 

N,N -Bis(/3phosphoric acid amide dichloride Cyclophosphamide Defosfamide T rofosfamide... 

German investigators (Brock et al) worked on the creation of alkylating pro-drugs that have cytostatic activity after specific biotransformation in the tumor tissue. Cyclophosphamide (CTX) has well pronounced antitumor activity with the broadest spectrum. It is metabolized to the cytotoxic phosphoamide mustard. In normal tissues with high enzyme level cyclophosphamide is converted to its inactive metabolites (Fig. 2). These differences in biotransformation can explain the relative selectivity of cyclophosphamide towards... 

Alkylating Agents. Figure 2 Biotransformation of cyclophosphamide - formation of inactive ( ) and toxic ( metabolites. 

Ifosfamide is an isomeric form of cyclophosphamide with analogous mode of action. 

Clinical trials showed therapeutic efficacy in a broad spectrum of tumors these include SCLC, testicular tumors, sarcomas, breast cancer, renal cell cancer, pancreatic tumors and lymphomas. Ifosfamide is less myelosuppressive than cyclophosphamide but is more toxic to the bladder. Therefore it is recommended that ifosfamide is coadministered with the thiol compound mesna to avoid hemorrhagic cystitis and to reduce the risk of developing bladder cancer. Other side effects include neurotoxicity and myelosuppression. 

Thiotepa is chemically less reactive than the nitrogen mustards. It has antineoplastic activity against ovarian and breast cancers as well as lymphomas. However, it has been largely supplanted by cyclophosphamide and other nitrogen mustards. 

Few side effects can be alleviated by the use of antidotes. An example is the prevention of hemorrhagic cystitis caused by cyclophosphamide by the concomitant infusion of mesna. 

O Brien S, Moore JO, Boyd TE et al (2007) Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 25(9) 1114-1120... 

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