H

Dihydrofluorouracil (DHFU)

FIGURE 2.23 Approaches to a decreased degradation of 5-FU.

5-FU prodrug ftorafur.24 Alternatively, the coadministration of 5-FU with DPD inhibitors, such as 5-chloro-2,4-dihydroxypyridine (CDHP, gimestat) and enilur-acil (5-ethynyluracil),25 is being investigated, as well as the use of the UFT combination plus DPD inhibitors.26 Eniluracil has received FDA orphan drug designation for its use in combination with fluoropyrimidines in the treatment of hepatocellular cancer.

4.4.2. Enhancement of the inhibition of TS by 5-FU

The action of TS requires the presence of 5,10-methylene-THF, and for this reason the coadministration of precursors of this cofactor increases the cytotoxicity of 5-FU in many cancer cell lines. For instance, the combination of 5-FU or ftorafur with leucovorin (LV, 5-formyl-THF) gave superior response rates than the single agents, and particularly the use of leucovorin to modulate UFT leads to a three-component combination called orzel that has been proposed as first-line chemotherapy of colorectal cancer.27 Leucovorin enters the cell via the reduced folate carrier (RFC) and is metabolized to 5,10-methylene-THF, without requiring the participation of DHFR, by cyclization to 5,10-methynyl-THF followed by NADP-mediated reduction of the iminium function (Fig. 2.24).

4.4.3. Enhancement of 5-FU activation

It has been proposed that pretreatment with methotrexate (MTX), an antifolate agent, enhances the activity of 5-FU28 because MTX inhibits the biosynthesis of tetrahydrofolic acid (THF), which is necessary for some steps of purine biosynthesis (see Section 6). This leads to accumulation of PRPP, essential for the activation of 5-FU, even though the levels of the TS cofactor should also be m u m u

5,10-Methylene-THF

FIGURE 2.24 Biotransformation of leucovorin into 5,10-methylene-THF.

5,10-Methylene-THF

FIGURE 2.24 Biotransformation of leucovorin into 5,10-methylene-THF.

diminished (see Section 4.4.2). Clinically, this combination has not always shown increased antitumor activity.29 On the contrary, several Phase II studies have shown a modest clinical benefit of 5-FU modulation utilizing MTX and leucovorin in patients with metastatic colorectal cancer.30

Diarrhea is the most common dose-limiting toxicity associated to prolonged infusion of 5-FU. In order to prevent this gastrointestinal toxicity, some oral formulations have been proposed that contain oxonic acid, a potent inhibitor of the phosphoriboxylation of 5-FU in the gastrointestinal mucosa. One of these formulations is S-1, which contains ftorafur, oxonic acid, and the previously mentioned gimestat (CDHP), an inhibitor of DPD (see Section 4.4.1).3 The basis for some of these combinations is summarized in Fig. 2.25.

4.5. Folate-Based TS inhibitors

As previously mentioned, TS inhibition by the fluoropyrimidines is not specific because of the effect of fluorinated nucleotides on other pathways, especially related to RNA (Figs. 2.15 and 2.18). Also, the accumulated dUMP may compete with the antitumor drug for TS. For this reason, there has been much interest in the design of inhibitors that recognize the folate-binding site of TS, which should not have these shortcomings and thus behave as specific TS inhibitors. Four of them (raltitrexed, pemetrexed, ZD-9331, and nolatrexed) have reached therapeutic use o co2h

Purine biosynthesis inhibition <

Accumulation

o co2h co2h

Methotrexate (MTX)

Methotrexate (MTX)

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment