Fluorocytosine 5FC 5fluorouracil 5FU

Fig. 4. Metabolism of 5-fluorocytosine. Generation of 5-fluorouracil (5-FU) from 5-fluorocytosine (5-FC) by the E. coli cytosine deaminase (CD) enzyme.

HSV-TK/GCV, because the capacity to form gap junctions appears to be lost in most cancer cells (58).

Two studies of CD/5-FC in experimental brain tumors have been performed using adenovirus (59,60). Stereotactic injection of adenovirus expressing CD into established gliomas derived from rat glioma cell lines in syngeneic hosts or human glioma cell lines in immunodeficient mice, followed by systemic administration of 5-FC, resulted in 160% (rat cells) and 137% (human cells) increases in survival time over controls. Treated rodents that died prior to the conclusion of the study showed no histologic signs of viable tumor. In the rat study, large areas of tumor necrosis were surrounded by extensive cerebral edema, suggesting that the strong bystander effect of CD/5-FC gene therapy caused toxicity to surrounding normal tissue and resulted in treatment-related death (59). No such edema was found in the study of human cell lines, a study in which the host rodents were immunodeficient (60).

Four CD/5-FC clinical trials are under way to treat metastatic colon carcinoma of the liver, metastatic breast cancer, prostate cancer, and penile cancer, with no results as of September 2001 (3). Cytochrome P450 2B1/Cyclophosphamide

Cyclophosphamide (CPA) is one of the most commonly used chemothera-peutic agents. CPA is a prodrug activated by liver-specific enzymes of the cytochrome P450 family. One of these, the rat cytochrome P450 2B1 (CYP2B1), activates CPA with high efficiency (61). This cytochrome hydroxylates CPA, forming 4-hydroxy-cyclophosphamide, an unstable compound that rapidly decomposes into phosphoramide mustard (PM) and acrolein (61). The former is an alkylating agent responsible for the biologic effects of CPA (61). PM-induced DNA alkylation generates intrastrand and interstrand DNA crosslinks. Toxicity occurs because attempting to replicate crosslinked DNA leads to strand breaks. PM alkylates DNA regardless of whether or not a cell is replicating, but toxicity does not occur until replication is attempted, assuming DNA repair has not occurred (Fig. 5).

The efficacy of CPA in treating tumors of the central nervous system has been limited by the fact that, although CPA crosses the blood-brain barrier, its active metabolites can only be generated by liver P450, and these metabolites are h h/^ cl n_p. ) Cytochrome cl o—/ p450 ci

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