Anticancer drugs cyclophosphamide

A good example of a compound that is a teratogen and requires metabolic activation is the anticancer drug cyclophosphamide, which has been studied extensively both in vivo and in vitro. 

Mesna is used to prevent or ameliorate hemorrhagic cystitis produced by the anticancer drugs cyclophosphamide and ifosfamide. It is excreted by the kidney and binds and detoxifies acrolein in the urine mesna also prevents the breakdown of acrolein precursors. It is also used as a mucolytic. 

An example of application of Fe(III) porphyrins is the hydroxylation of the anticancer drug cyclophosphamide to active metabolite 4-hydroxycyclophosphamide in yields similar or higher than those typically obtained by the action of liver enzymes in vivo [198]. This allows the development of novel anticancer drugs for the treatment of tumors with less toxic side effects to the patient. There are many other examples of metalloporphyrin-based systems for the synthesis of drugs or agrochemicals that mimic P450 catalyzed processes. 

Figure 1. Activation reactions for the anticancer drugs cyclophosphamide and cisplatin.

The much used anticancer drug, cyclophosphamide 3.31) is inert until converted to the active agent by hepatic e.r. Some workers think that this active agent is the 4-hydroxy-derivative formed by metabolism (Takamizawa et al., 1975), but metabolism continues right down to the acyclic derivative (3.32), and this, or something in between, may be the true drug (Connors et al., 1974). 

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). 

Novel nitroxide malonate methanofullerenes (Fig. 1.3), thanks to the presence of nitroxide radicals and fullerene moiety, are able to protect cells from toxic side effects of cyclophosphamide (Gubskaya et al., 2007). Experiments were carried out on mice, in which leukemia P-388 was transplanted. Cyclophosphamide or fullerene individually injected did not increase the average life span of the animals, while the combination of the anticancer drug and nitroxide fullerene derivative resulted in the survival of 70% animals, classifying these compounds as promising modifiers of biological reaction for tumor therapy. 

Most anticancer drugs damage hair follicles and produce partial or complete alopecia. Patients should be warned of this reaction, especially if paclitaxel, cyclophosphamide, doxorubicin, vincristine, methotrexate, or dactinomycin is used. Hair usually regrows normally after completion of chemotherapy. 

Drugs that cause damage to proliferating cells such as those in bone marrow, will cause a similar effect to benzene. Thus cyclophosphamide, the anticancer drug, inhibits the clonal expansion of T- and B-cell precursors in the bone marrow and causes anemia. 

Some common anticancer drug combinations and the types of cancer in which they are used are listed in Table 36-8. These drug combinations are often indicated by an acronym of the drug names. For instance, FAC indicates a regimen of fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide. These abbreviations are used to summarize drug therapy in a patient s medical chart, so therapists should be aware of the more common chemotherapy combinations. 

In animal studies, NAC has been shown to prevent hemorrhagic cystitis that results from administration of cyclophosphamide or its position isomer ifosfamide. Hemorrhagic cystitis results from the toxic effect of acrolein, a metabolic product of cyclophosphamide or its position isomer ifosfamide. The mechanism whereby NAC prevents this toxicity may be prevention of the intracellular depletion of antioxidants, such as GSH, by acrolein. Concomitant administration of NAC with cyclophosphamide or ifosfamide does not impair antineoplastic activity, because both anticancer drugs are inactive until they are metabolized by the liver to their phosphoramide mustard metabolites. 

Electrochemical oxidation of anticancer drugs ifosfamide and cyclophosphamide produced in high yield methoxylated analogues of the key hydroxy-metabolites of these oxazaphosphorine prodrugs (Scheme 19). ... 

Mechanism-based inactivation of CYP450 (or suicide inhibition) occurs when a non-toxic drug is metabolised by CYP450 to generate a metabolite that can bind irreversibly with the enzyme. The mechanism of inhibition usually involves free-radical alkylation or acylation of the active site and results in destruction of enzyme activity. Examples of drugs that act in this way include the antibiotic chloramphenicol and the anticancer agent cyclophosphamide. 

Anticancer chemotherapies Azathioprine, cyclophosphamide, methotrexate etc. The cytotoxic substances affect proliferating cells and hematopoiesis as well as lymphocyte proliferation are especially sensitive. Association with risk of clinical infections clearly established. 1 % of chemotherapy patients develop an independent cancer within 10 years, 3 % within 20. Noteworthy, some anticancer drugs are now used also as immunosuppressant for autoimmune diseases... 

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