Fludarabine phosphate is rapidly dephosphorylated to 2-fluoroarabinofuranosyladenosine and then phosphorylated intra-cellularly by deoxycytidine kinase to the monophosphate, which is eventually converted to the triphosphate. Fludarabine triphosphate interferes with the processes of DNA synthesis and DNA repair through inhibition of DNA polymerase-α and DNA polymerase-β. The triphosphate form can also be directly incorporated into DNA, resulting in inhibition of DNA synthesis and function. The diphosphate metabolite of fludarabine inhibits ribonucleotide reductase, leading to inhibition of essential deoxyribonucleotide triphosphates. Finally, fludarabine induces apoptosis in susceptible cells through as yet undetermined mechanisms. This purine nucleotide analog is used mainly in the treatment of low-grade non-Hodgkin’s lymphoma and chronic lymphocytic leukemia (CLL). It is given parenterally, and up to 25–30% of parent drug is excreted in the urine. The main dose-limiting toxicity is myelosuppression. This agent is a potent immunosuppressant with inhibitory effects on CD4 and CD8 T cells. Patients are at increased risk for opportunistic infections, including fungi, herpes, and Pneumocystis jiroveci pneumonia (PCP). Patients should receive PCP prophylaxis with trimethoprim-sulfamethoxazole (double strength) at least three times a week, and this should continue for up to 1 year after stopping fludarabine therapy.
Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analog with high specificity for lymphoid cells. Inactive in its parent form, it is initially phosphorylated by deoxycytidine kinase to the monophosphate form and eventually metabolized to the triphosphate form, which can then be incorporated into DNA. The triphosphate metabolite can also interfere with DNA synthesis and DNA repair by inhibiting DNA polymerase-α and DNA polymerase-β, respectively. Cladribine is indicated for the treatment of hairy cell leukemia, with activity in other low-grade lymphoid malignancies such as CLL and low-grade non-Hodgkin’s lymphoma. It is normally administered as a single continuous 7-day infusion; under these conditions, it has a very manageable safety profile with the main toxicity consisting of transient myelosuppression. As with other purine nucleoside analogs, it has immunosuppressive effects, and a decrease in CD4 and CD8 T cells, lasting for over 1 year, is observed in patients.
The vinca alkaloids inhibit the process of tubulin polymerization, which disrupts assembly of microtubules, especially those involved in the mitotic spindle apparatus. This inhibitory effect results in mitotic arrest in metaphase, bringing cell division to a halt, which then leads to cell death. Thus, the vinca alkaloids work in the M phase of the cell cycle. Microtubules also play an important role in maintaining cell shape and cellular motility, and they facilitate the intracellular transport of cellular proteins. As such, inhibition of microtubule formation has important consequences that can lead to cell death.
The main adverse effects are outlined in Table 54–4, and they include nausea and vomiting, bone marrow suppression, and
Vinblastine is an alkaloid derived from the periwinkle plant alopecia. This agent is also a potent vesicant, and care must
Vinca rosea. Vinblastine and other vinca alkaloids are metabo be taken in its administration. It has clinical activity in the lized by the liver P450 system, and the majority of the drug treatment of Hodgkin’s and non-Hodgkin’s lymphomas, breast is excreted in feces via the hepatobiliary system. As such, dose cancer, and germ cell cancer.