Gemcitabine, adverse effects

Gemcitabine is intracellularly activated by nucleoside kinases to diphosphate and triphosphate nucleosides. Gemcitabine diphosphate inhibits DNA synthesis by inhibiting ribonucleotide reductase while gemcitabine triphosphate competes with deoxycytidine triphosphate for incorporation into DNA. Gemcitabine is used for the treatment of non-small cell lung carcinoma and of adenocarcinoma of the pancreas. It has to be administred intravenously and is eliminated by metabolism with an elimination half-life of approximately 50 minutes. Its spectrum of adverse effects is comparable to that of 5-FU. 

Adverse effects Myelosuppression is the dose-limiting toxicity of gemcitabine. Other toxicities are nausea, vomiting, alopecia, and rash. Transient elevations of serum transaminases, proteinuria, and hematuria are common. Resistance to the drug is probably due to its inability to be converted to a nucleotide the tumor cell produces increased levels of endogenous deoxycytidine that compete for the kinase, thereby by-passing the inhibition. 

Hematologic Myelosuppression was the main dose-limiting adverse effect of gemcitabine in phase I studies, and it particularly caused thrombocytopenia and anemia [51 ]. In 979 patients in 22 phase II trials the rates of grade 3/4 thrombocytopenia, anemia, leukopenia, and neutropenia were 5.2%, 8%, 9%, and 25% respectively [46 ]. The withdrawal rate because of hematological adverse events was under 0.6%. Although there is no evidence of cumulative toxicity, patients who have received previous cytotoxic chemotherapy or are receiving combination chemotherapy are more likely to have severe myelosuppression and be at risk of febrile neutropenia [52 ], which occurs in up to 10% [34 ]. 

Liver In phase I studies, reversible rises in aminotransferases were among the principal adverse effects of gemcitabine [53 ]. Such rises occur in about 70% of patients but are usually transient and there is no evidence of cumulative hepatic toxicity [46 ]. Raised alkaline phosphatase and bilirubin are less common. Among patients with underlying liver dysfunction, those with baseline rises in bilirubin, but not aminotransferases, may develop more marked increases in both aminotransferases and bilirubin during therapy [54 ]. As a result, it is recommended that the initial dose should be 800mg/m, with dose escalation depending on tolerance. Very... 

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