HO' GCV MP
FIGURE 23.1 Herpes simplex virus thymidine kinase (HSVtk); ganciclovir (GCV), monophosphate (MP); triphosphate (TP).
in culture and in vivo . Possible explanations for radiation enhancement is that DNA which has incorporated acyclovir may be susceptible to radiation-induced strand breakage, and/or acyclovir might sensitize cells by inhibiting polymerase activity required for the repair of radiation-induced DNA damage.
Several strategies have been developed in attempting to improve tumor cell killing. One method involves generating novel and enzymatically enhanced HSVtk mutants to induce an increased sensitivity to GCV in transfected cells . The delivery of GCV was also improved by using biocompatible silicones that were directly implanted into the gliomas of experimental rodent models. The results revealed a hundredfold drug concentration over GCV that had been administered intraperitoneally . One approach using a replication-defective herpes simplex virus type 1 vector (NUREL-C2) combines three strategies in order to improve tumor cell killing. The base vector expresses HSVtk, and human tumor necrosis factor alpha with coexpression of the gap-junction-forming protein connexin43. This vector has been shown to be effective in treating animal models of glioma [23,24]. The HSVtk/GCV ''CLINICAL TRIALS'' for brain tumors are discussed in section clinical trials of this chapter.
used to treat cancers like colon, pancreatic, and breast cancer. The cytotoxic effects of 5-FU occur following its conversion to 5-fluoro-2'-deoxyuridine-5'-monophosphate (5-FdUMP). 5-FdUMP is an irreversible inhibitor of thymidylate synthase and thus inhibits DNA synthesis by deoxythymidine tripho-sphate (dTTP) deprivation and causes DNA strand breakage, leading to cell death .
Rodent gliosarcoma cells expressing the E. coli CD gene become 77 times more sensitive to 5-FC in culture . In addition, tumor cells expressing CD may present CD peptides on MHC class I, where they could lead to an immune response . In order to improve tumor cell killing, a strategy has been developed, where the therapeutic vector encompassed two suicide genes to sensitize cells doubly to GCV and 5-FC [26,28]. In contrast to the HSVtk/GCV approach, 5-FU metabolites do not require cell-cell contact for a bystander effect. On cell lysis, 5-FU is released into the medium and is thus likely to be responsible for the bystander effect, and indeed the 5-FU levels in the medium correlated well with the degree of cytotoxicity . Animal studies of CD/ 5-FC using adenoviral vectors for rodent and human glioma cell lines showed an increase in survival time compared to controls . From the CD/5-FC clinical trials underway none is for brain tumors.
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