Exploitation of elevated pyrimidine deaminating enzymes for selective chemotherapy

A role for DNA mismatch repair in sensing and responding to fluoropyrimidine damage

“…In fact, Mekras et al (1984Mekras et al ( , 1985 showed that FdCyd was more effective on a molar basis in vivo than 5-FU or FdUrd and exhibited more tumor cell-directed cytotoxicity. This higher efficiency was partially (Mekras et al, 1985;Boothman et al, 1987a). Subsequent studies showed that fluorinated cytidine compounds, when modulated with the dCyd deaminase (dCydD) inhibitor tetrahydrouridine (H 4 Urd), could deliver as much as three to four orders of magnitude higher levels of FdUMP to tumor tissue versus normal tissue (Mekras et al, 1984;Boothman et al, 1987a, b).…”

“…FdCyd antimetabolites can be acted upon by deaminases specifically elevated in CRCs, thereby effectively delivering FdUrd to DNA in tumors (Mekras et al, 1984;Kaysen et al, 1986;Boothman et al, 1987b). In fact, Mekras et al (1984Mekras et al ( , 1985 showed that FdCyd was more effective on a molar basis in vivo than 5-FU or FdUrd and exhibited more tumor cell-directed cytotoxicity.…”

“…This occurs because H 4 Urd can inhibit the conversion of FdCyd to FdUrd and instead channel its conversion to FdCMP, whereby (following deamination) it is converted to FdUMP at high levels, causing greater TS inhibition and cytotoxicity than FdCyd alone (see Figure 4). (Mekras et al, 1984(Mekras et al, , 1985Boothman et al, 1985;Kaysen et al, 1986). In addition to being able to modulate FdCyd metabolism in tumor tissue selectively, FdCyd is a powerful hypomethylating agent.…”

“…Although not yet tested in humans, 5-fluoro-2-deoxycytidine (FdCyd) has exhibited promise for tumor therapy in animal models (Mekras et al, 1984;Boothman et al, 1987a). FdCyd antimetabolites can be acted upon by deaminases specifically elevated in CRCs, thereby effectively delivering FdUrd to DNA in tumors (Mekras et al, 1984;Kaysen et al, 1986;Boothman et al, 1987b).…”

Mechanism of inhibition of DNA methyltransferases by cytidine analogs in cancer therapy

“…46,47 5-fluoro-2'-deoxycytidine (5-FCdR) also inhibits DNA methylation and reactivates silenced genes when incorporated in DNA 48 but has a lesser potential as a drug since it generates potentially toxic products: 5-fluorodeoxyuridine and its metabolites. 49 …”