Substrate for dCTP/triphosphate




(prodrug of 5-FU)



Inhibits ribonucleotide reductase




(prodrug of decitabine)



Inhibits DNA methyltransferase




(prodrug of guanine arabinoside)

Triphosphate of guanine arabinoside



Inhibits thymidylate synthase




Inhibits DNA polymerases

Triphosphate 5-Fluorouracil/Leucovorin

The standard of care for many carcinomas for several years was 5-FU. Although 5-FU is widely used, its pharmacokinetic (PK) profile is not ideal. Its optimal method of delivery is by continuous intravenous infusion, as its bioavailability after oral administration is variable. 5-FU is rapidly metabolized, with a mean half-life (t1/2) of elimination of approximately 16min. Within 3h, no intact drug can be detected in plasma. 5-FU is more effective when coadministered with folinic acid (also referred to as LV or leucovorin), a prodrug of 5,10-CH2-THF. Inhibition of TS by the 5-FU metabolite 4 is dependent on the cofactor 5,10-CH2-THF which combines with TS and 4 to form a covalent ternary complex. Excess cofactor decreases the dissociation rate of this complex, and consequently addition of leucovorin increases the cytotoxicity of 5-FU. The major toxicities of 5-FU are to bone marrow and mucous membranes.34 Capecitabine

Capecitabine (6) is an orally administered fluoropyrimidine carbamate that is metabolized in vivo to 5-FU (3). PK studies in patients showed rapid gastrointestinal absorption of capecitabine, followed by extensive conversion to 8, with only low systemic levels of 5-FU.36 In preclinical animal models, capecitabine appeared to deliver drug selectively to tumors. Analysis of the tumor: plasma area under curve (AUC) ratios of capecitabine versus 5-FU in four human tumor xenografts in mice (HCT116, CXF280, COLO205, and WiDr) at the maximum tolerated dose (oral) showed that although the t1/2 of 5-FU was similar in all four tumors, the tumor: plasma AUC ratio of 5-FU was significantly higher for animals dosed with capecitabine. For example, in HCT116, 5-FU exposure was 127-fold higher in tumor than plasma in animals treated with capecitabine, and 209-fold higher in CXF280. In addition, the AUCinf of 5-FU in tumor via capecitabine dosing was 18- to 32-fold higher than via direct 5-FU dosing, demonstrating that capecitabine is efficiently converted to 5-FU in the tumors.37 In the clinic, the efficacy of capecitabine equals or exceeds 5-FU, and some differences in tumor versus adjacent tissue exposure are observed, although not to the same extent as in the murine models.38 In colorectal tumors, the concentration of 5-FU was found to be 3.2-fold higher in the tumor than in the adjacent healthy tissues. In liver metastasis, however, no difference in exposure was found between the diseased and healthy tissues. The tumor-preferential activation of capecitabine to 5-FU is explained by tissue differences in the activity of cytidine deaminase and thymidine phosphorylase, key enzymes in the capecitabine — 5-FU conversion. The interpatient variability in AUC and Cmax (from 27% to 89%) is also attributed to the different levels of expression of the same enzymes across the patient population.

The elimination t1/2 of parent capecitabine in the phase III studies ranged from 0.55 to 0.89 h, and it reached its peak plasma concentration (tmax) in 2h. Thus, the t1/2 of capecitabine after oral administration of 1250 mgm_ 2 is comparable to that of 5-FU, but its ease of dosing by mouth offers an advantage to patients. Capecitabine is approved for the treatment of breast and colorectal cancer. Gemcitabine

Gemcitabine (11) is a nucleoside analog that exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S phase) and also blocking the progression of cells through the G1/S phase boundary. The cytotoxic effect of gemcitabine is attributed to the actions of both its diphosphate and the triphosphate nucleosides, which leads to inhibition of DNA synthesis. First, gemcitabine diphosphate inhibits NDPR, which causes a reduction in the concentrations of deoxynucleotides, including deoxycytidine triphosphate (dCTP).39 Second, gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP (by the action of the diphosphate) enhances the incorporation of gemcitabine triphosphate into DNA (self-potentiation). Following gemcitabine nucleotide incorporation into DNA, only one additional nucleotide is added to the growing DNA strand, followed by inhibition of further DNA synthesis. Because of the addition of this final nucleotide, DNA polymerase epsilon is unable to remove the gemcitabine nucleotide and repair the growing DNA strands (masked chain termination).40

Gemcitabine has been approved in the USA for use either as a single agent or in combination for three carcinomas: pancreatic, NSCLC, and breast (Table 6). First approved by the FDA in 1996, gemcitabine was demonstrated to have a significant clinical benefit response in advanced pancreatic cancer patients compared to 5-FU, with a survival advantage of 5.6 months versus 4.4 months in the 5-FU treated patients.31 The clinical benefit was measured as improvement in three symptoms present in most pancreatic cancer patients: pain, functional impairment, and weight loss. Gemcitabine has become accepted as the standard of care for the treatment of advanced pancreatic cancer, and in 1998 the FDA approved its combination with cisplatin for the treatment of NSCLC.41 The gemcitabine/cisplatin combination demonstrated a survival advantage of 9.0 months versus 7.6 months for cisplatin alone, and increased the median time to disease progression by 1.5 months. In 2004, gemcitabine was approved for use in breast cancer in combination with paclitaxel, with a significant increase in time to disease progression from 2.9 months for paclitaxel alone to 5.2 months for the gemcitabine/paclitaxel doublet.

The PK parameter of elimination t1/2 for gemcitabine is similar to that of 5-FU.42 In a population study of 353 patients, t1/2 ranged from 42 to 92 min, with significant age and gender differences. The longest t1/2 of 92 min was observed for women over age 75, and the shortest was for men under age 30. Clearance decreased with age and gender and was approximately 25% less for women than men, regardless of age. The average clearance value of 87.5 Lh _ 1 kg_ 1 indicates a two-compartment model of metabolism in which tissues in addition to liver contribute to metabolism.

Clinical trials are ongoing for other indications, including ovarian, bladder, and non-Hodgkin's lymphoma (NHL),43 employing gemcitabine as a single agent or in combination with other drugs. Trials with gemcitabine monotherapy as a

Table 6 Gemcitabine activity in solid tumors (approved indications in USA)


Gemcitabine or gemcitabine + SOC40

Standard of care (SOC)

Pancreatic cancer


0 0

Post a comment