FLUOROPYRIMIDINES

5-Fluorouracil (5-FU) is an analogue of uracil that is con­verted by multiple alternative biochemical pathways to several cytotoxic forms.  It is converted to 5-fluoro-2-deoxyuridine (FUDR) by the enzyme thymidine phospho-rylase,  and  subsequent  phosphorylation  by thymidine kinase results in the formation of 5-fluoro-deoxyuridine monophosphate (FdUMP). In the presence of reduced folate, FdUMP forms a stable covalent complex with TS, which is also a key enzyme in the de-novo synthesis of the pyrimidine   deoxynucleotide,   deoxythymidine   triphos-phate (dTTP), a direct precursor for the synthesis of DNA. This inhibition of TS is considered to be the main mecha­nism for the action of 5-FU, although nucleotides of 5-FU can also be incorporated directly into both DNA (5-fluoro-2-deoxyuridine-5-triphosphate, FdUTP) and RNA (fluo-rouridine triphosphate, FUTP). The TS-FdUMP complex is slowly dissociable, with a half-life of 6 hours, and the expression of TS is cell-cycle dependent, with high activity during the S phase. Also, as the presence of reduced folate is critical for TS-FdUMP complex formation, depletion of intracellular reduced folates impairs the maintenance of TS inhibition.   Co-administration  of leucovorin  has  been shown to increase the duration of TS inhibition and enhance the cytotoxic effect of 5-FU.

The pharmacology of 5-FU is complex and character­ized by erratic oral bioavailability, non-linear elimination pharmacokinetics and significant intra/inter-patient vari­ability. Clearance is rapid, especially when given by bolus injection, with a half-life of 15 minutes. Several random­ized trials have demonstrated the advantage of continuous infusion over bolus injection, but this is at the expense of considerable patient inconvenience (with the requirement of an indwelling central venous catheter) and increased cost The main uses are in the treatment of breast and gastrointestinal cancers. Toxic effects include nausea, diarrhoea, mucosal inflammation and moderate myelo-suppression. Infusional schedules also increase the inci­dence of plantar-palmar erythrodysaesthesia (hand-foot syndrome).

The development of oral fluoropyrimidines is proceed­ing apace, with the aim to deliver optimal 5-FU to the tumour in a convenient and controlled fashion while min­imizing the variability and clearance. Capecitabine is an orally available tumour-selective fluoropyrimidine carba-mate. Following administration, it is bioactivated to 5-FU by a cascade of three enzymatic reactions. After oral administration it passes unchanged through the gastrointest inal tract and is metabolized in the liver by carboxylesterase to 5-deoxy-5-fluorocytidine (5-DFCR). Then it is con verted to 5-deoxy-5-fluorouridine (5-DFUR) by cytidine deaminase in liver and also tumour tissues. Further metab olism of 5-DFUR occurs selectively within tumours by thymidine phosphorylase (dThdPase) to 5-FU, thus mini­mizing the exposure of normal tissues to systemic 5-FU. Side effects resemble those seen with infusional 5-FU and are reversible; severe (grade III/IV) toxicities were shown to be infrequent and manageable with subsequent dose modification. The events observed most often were diar rhoea, nausea, hand-foot syndrome, vomiting, fatigue and stomatitis. Capecitabine is used in gastrointestinal and breast cancers.

The enzyme dihydropyrimidine dehydrogenase (DPD) is the rate-limiting step for the catabolism of 5-FU, and converts more than 85 per cent of clinically administered 5-FU into inactive metabolites. It is primarily responsible for the high systemic clearance and short half-life of this drug, and therefore limits the amount of 5-FU available for conversion to the most active cytotoxic metabolite, 5-FUTP. DPD is found in many human tumours, but also in normal tissues, including the liver and the intestines, where it is largely responsible for the erratic bioavailability of 5-FU. Pharmacological inhibition of DPD may therefore increase the therapeutic index and efficacy of oral 5-FU, by allowing consistent dose delivery, eliminating hepatic clearance and producing more predictable drug clearance through the renal tract. In addition, over-expression of DPD in tumour cells may result in rapid intracellular fluoropyrimidine destruction and increased resistance to 5-FU. It is theoret­ically possible that the oral administration of fluoropyrim-idines together with DPD inhibitors may overcome clinical drug resistance.

In contrast to capecitabine, which is absorbed as an inactive pro-drug, other novel oral fluoropyrimidine for­mulations are co-administered with inhibitors of DPD in order to produce an improved pharmacokinetic profile for 5-FU. These compounds include UFT (uracil/Tegafur), eniluracil, S-l and BOF-A2. These novel agents all deliver a therapeutic advantage from DPD modulation, and permit safe and effective 5-FU administration.

PURINE ANALOGUES

6-Mercaptopurine (6-MP) is an analogue of the natural purine base hypoxanthine. It is converted by the enzyme hypothine-guanine phosphoribosyl transferase to the active nucleotide 6-mercaptopurine ribose phosphate, which inhibits de-novo purine synthesis. The triphosphate nucleotides also incorporate into DNA, causing strand breakage. 6-MP is absorbed well orally, and broken down by hepatic xanthine oxidase to inactive metabolites, with half the dose excreted within 24 hours. Allopurinol can inhibit this enzyme, and therefore if both drugs are co-administered, care is needed in order to reduce the risk of increased tox-icity. Toxicity includes emesis, myelosuppression and a hepatic toxicity characterized by cholestatic jaundice.

6-Thioguanine (6-TG) is an analogue of guanine and has a similar mechanism of action to 6-MP. However, xan­thine oxidase is not involved in its metabolism, and there­fore there is no interaction with allopurinol. Again, oral administration is used, and the main indications are in haematological cancers.

PYRIMIDINE ANALOGUES

Cytarabine (cytosine arabinoside; Ara-C) is an analogue of deoxycytidine isolated from the sponge Cryptothethya crypta. It follows the same metabolic pathways of its physio­logical counterpart, and thus requires to be transported to the cell for activation. Cytarabine triphosphate (ara-CTP) is the cytotoxic metabolite of cytarabine, and acts via inhibition of DNA replication and repair and by incorporation into the DNA. Because of this, it is consid­ered as an S-phase-specific drug, although it is active at other phases of the cycle. The main use is in the treatment of lymphoma and leukaemia, and it is given by intravenous injection because it is affected by first-pass metabolism if given orally. Intrathecal cytarabine is administered in the treatment of meningeal leukaemia and carcinomatosis. Toxicities include myelosuppression, emesis and diarrhoea. Syndromes of pulmonary toxicity and neurological toxicity occur rarely.

Gemcitabine (2,2-difluorodeoxycytidine) is a pyrimi-dine analogue structurally similar to cytarabine. The metabolism differs in that accumulation of its active cyto­toxic metabolite is higher than ara-CTP, and its elimina­tion is much more prolonged. The mechanism of activity is similar, consisting of incorporation into DNA and inhibi­tion of DNA synthesis. However, gemcitabine can also be incorporated into RNA. Toxicity is relatively low, consist­ing of myelosuppression, lethargy, flu-like symptoms and a skin rash. A rare pulmonary toxicity is also thought to be implicated. Gemcitabine is active in many pre-clinical solid-tumour models, and has demonstrated clinical activity against ovarian, gastrointestinal, breast, bladder and non-small-cell lung cancers. Furthermore, pre-clinical evidence for synergism has been demonstrated with several other cyto­toxic agents, including cisplatin, etoposide and mitomycin C.

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