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Gemcitabine Mechanism Of Action

gemcitabine mechanism of action

Abstract

gemcitabine (dfdc) is a new anticancer nucleoside that is an analog of deoxycytidine. it is a pro-drug and, once transported into the cell, must be phosphorylated by deoxycytidine kinase to an active form. both gemcitabine diphosphate (dfdctp) and gemcitabine triphosphate (dfdctp) inhibit processes required for dna synthesis. incorporation of dfdctp into dna is most likely the major mechanism by which gemcitabine causes cell death.

after incorporation of gemcitabine nucleotide on the end of the elongating dna strand, one more deoxynucleotide is added and thereafter, the dna polymerases are unable to proceed. this action ("masked termination") apparently locks the drug into dna as the proofreading enzymes are unable to remove gemcitabine from this position. furthermore, the unique actions that gemcitabine metabolites exert on cellular regulatory processes serve to enhance the overall inhibitory activities on cell growth. this interaction is termed "self-potentiation" and is evidenced in very few other anticancer drugs.

Mechanism of action & dosage

Despite the similarities in structure, metabolism and mechanism of action with Ara-C, the spectrum of antitumor activity of gemcitabine is much broader. The most commonly used schedule in clinical practice is 1000 mg/m2 intravenously administered weekly for 3 weeks, followed by 1 week rest. This schedule seems to provide the most acceptable toxicity profile with the greatest dose intensity.

Toxicity

Gemcitabine has been used in a wide variety of malignancies, both as a single agent and in combination with other cytotoxic drugs. Although gemcitabine is a relatively well-tolerated drug when used as a single agent, its toxicity profile can vary significantly according to the schedule of administration. Using the standard 30-minutes infusion, World Health Organization (WHO) grade 3 and 4 anemia occurs in 9.9 and 1.6% of cases, respectively. WHO grade 3 and 4 neutropenia occur in 11.5 and 2.9% of cases, respectively, and neutropenic fever is a rare event. WHO grade 3 thrombocytopenia occurs in 6.0% of patients and grade 4 in less than 4.0%, with hemorrhage reported in 0.6% of cases.

Drug interactions

No specific drug interaction studies have been conducted. Gemcitabine has been combined with various chemotherapeutic compounds in the treatment of several solid tumors. Cisplatin (CDDP) is one of the agents most commonly used in combination with gemcitabine, and in vitro studies have shown synergistic interactions between the two drugs. This synergism is thought to be mainly due to an increase in platinum–DNA adduct formation.

Gemcitabine in pancreatic cancer

There are few therapies with proven benefit against pancreatic cancer. Gemcitabine was approved as first-line treatment for pancreatic cancer on the basis of a randomized study comparing weekly gemcitabine with weekly 5-fluorouracil (5-FU) that demonstrated an improvement in median survival, 1-year survival and clinical benefit. This study has been criticized because the control arm of FU was not delivered optimally.

Conclusions

Gemcitabine is one of the most active agent in cancer treatment, approved for the treatment of NSCLC, pancreatic, bladder, and breast cancer, and the recent data presented in ovarian cancer will lead to approval also in ovarian cancer. Due to the low toxicity profile, the drug can be a valid alternative for unfit and elderly patients. Recent data failed to demonstrate any advantage when gemcitabine-based regimens were combined with new targeted agents, such as the tyrosine kinase inhibitors gefitinib and erlotinib.

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