Gemcitabine is a commonly used antineoplastic agent that is a nucleoside analog and pyrimidine antimetabolite that inhibits rna synthesis. Read does saturable formation of gemcitabine triphosphate occur in patients. Gemcitabine exerts its cytotoxic effect mainly through inhibition of dna synthesis by being incorporated into the dna strand as the active dfdctp. By inhibiting this enzyme, the intracellular deoxyribonucleotide triphosphate dntp pool is depleted. Gemcitabine may potentiate fluorouracils inhibition of thymidylate synthase. Subsequent dosing cycles iv 1 gm 2 once weekly for 3 consecutive weeks, followed by a week of rest from treatment. Xu, yz flavopiridol increases sensitization to gemcitabine in human gastrointestinal cancer cell lines and correlates with downregulation of ribonucleotide reductase m2 subunit. Gemcitabine metabolism and mechanism of action gemcitabine is transported into cells by sodiumdependent concentrative nucleoside transporter hcnts and sodiumindependent equilibrative nucleoside transporter hents mechanisms. Ribonucleotide reductase is inhibited by gemcitabine diphosphate, an activity that leads to metabolic selfpotentiating effects. Gemcitabine is associated with a high rate of transient serum enzyme elevations during therapy but is a very rare cause of acute, clinically apparent liver injury. Gemcitabine requires phosphorylation to mono, di, and triphosphates dfdctp to be active. Combined gemcitabine and carboplatin therapy for carcinomas in dogs.
After the gemcitabine nucleotide is incorporated into dna, only one additional nucleotide is added to the growing dna strands. Preclinical absorption, distribution, metabolism, and. Phosphorylation of these agents to triphosphate forms by deoxycytidine kinase is required for direct inhibition of dna synthesis by incorporation with resultant chain termination 7. Cellular elimination of 2,2difluorodeoxycytidine 5triphosphate. The ability to deliver this agent as an oral drug would allow greater flexibility of administration and patient convenience. Purpose this phase iii trial compared the efficacy and safety of gemcitabine gem plus capecitabine gemcap versus singleagent gem in advancedmetastatic pancreatic cancer. A response rate of 19% was observed for singleagent gemcitabine within the german testicular cancer study group trial, and this result was independently confirmed by a study of the indiana. Oral administration of gemcitabine in patients with. The cytotoxic activity of gemcitabine may be the result of several actions on dna. Feb 16, 2011 posterior reversible encephalopathy syndrome is a clinicoradiologic entity that may present with headaches, altered mental status, seizures and visual loss as well as specific neuroimaging findings. Gemcitabine hydrochloride monograph for professionals. Gemcitabine dfdc is a new anticancer nucleoside that is an analog of deoxycytidine.
Its mechanism of action depends on phosphorylation and inhibition of the production of deoxynucleotide triphosphate required for normal dna synthesis. Gemcitabine exhibits the properties of selfpotention and masked chain termination. Mechanisms of action of nucleoside analogues and drug metabolism. Metabolism, mechanisms of action, and selfpotentiation, abstract gemcitabine dfdc is a new anticancer nucleoside that is an analog of deoxycytidine. Like other anticancer drugs, gemcitabine demonstrates high between. Gemcitabine hydrochloride 122111039 tci chemicals india. We also showed that administration of cx4945 on an intermittent schedule, that is, 24 hours after each dose of gemcitabine could enhance the efficacy of gemcitabine in mice. Nucleoside analogues and nucleobases in cancer treatment. This family of compounds has grown to include a variety of purine and pyrimidine nucleoside derivatives with activity in both solid tumours and malignant disorders of the blood. In general, the underlying mechanisms of chemoresistance are poorly understood. Microregional effects of gemcitabine in hct116 xenografts.
Gemcitabine induced reversible posterior leukoencephalopathy syndrome. To determine the toxicity, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of oral gemcitabine 2. This inhibition would be expected to be sequence dependent. These agents behave as antimetabolites, compete with physiological. Plunkett w, huang p, xu yz, heinemann v, grunewald r and gandhi v 1995 gemcitabine. Gemcitabine is a chemotherapy agent with efficacy in the treatment of lung, pancreas, bladder and breast cancer. This indirect inhibition of dctd by dfdcdp is due to a reduction in the intracellular dntp pool. Efficacy of gemcitabine in patients with nonsmall cell lung. Microbes contribute not only to the development of human diseases but also to the response of diseases to treatment. Phase i study of irinotecan and gemcitabine in previously. Tolerability of gemcitabine and carboplatin doublet.
This interaction is termed selfpotentiation and is evidenced in very few other anticancer drugs. Population pharmacokinetics of gemcitabine and its. The reduction in the intracellular concentration of dctp by the action of the diphosphate enhances the incorporation of gemcitabine triphosphate into dna selfpotentiation. Gemcitabine plus capecitabine compared with gemcitabine. Gemcitabine monotherapy associated with posterior reversible. These findings further illustrate that cx4945 prevents ck2 from activating dna repair response mechanisms, thereby preventing replication recovery.
Gemcitabine gemzar is an antimetabolite that is effective as monotherapy or in combination with other drugs in a variety of solid tumors. An additional mechanism of action of gemcitabine is selfpotentiation by inhibition of enzymes related to deoxynucleotide metabolism. Gemcitabine is an intravenously administered nucleoside analog chemotherapeutic agent. The clinical formulation is supplied in a sterile form for intravenous use only. Metabolism,mechanisms of action, and selfpotentiation. Urachal cancer urc is a very rare but highly malignant tumor with an incidence of gemcitabine has been studied in other trials against sarcomas. Patients and methods patients were randomly assigned to receive gemcap oral capecitabine 650 mgm2 twice daily on days 1 to 14 plus gem 1,000 mgm2 by 30minute infusion on days 1 and 8 every 3 weeks or gem 1,000 mg. Metabolism, mechanisms of action and selfpotentiation of gemcitabine. Vials of gemzar contain either 200 mg or 1 g of gemcitabine hcl expressed as free base formulated with mannitol 200 mg or 1 g, respectively and sodium acetate 12. Once inside the cell, gemcitabine is rapidly phosphorylated by deoxycytidine kinase to form the active metabolites gemcitabine diphosphate dfdcdp and gemcitabine triphosphate dfdctp. However, gemcitabinetreated patients with high tumoral rrm1 expression generally evidence poor prognoses due to the decreased efficacy of gemcitabine therapy.
Early studies in leukemic cells noted a dramatic effect of gemcitabine on dna metabolism. Efficacy of gemcitabine in patients with nonsmall cell. Intracellular pharmacokinetics of gemcitabine, its deaminated. Despite such broad use, intrinsic and acquired chemoresistance is common. The mechanism of action of gemcitabine is as a nucleic acid synthesis inhibitor. Does saturable formation of gemcitabine triphosphate occur in. Among other mechanisms of selfpotentiation, gemcitabine triphosphate inhibits deoxycytidine monophosphate deaminase, thereby decreasing triphosphate catabolism. Cytotoxic nucleoside analogues and nucleobases were among the first chemotherapeutic agents to be introduced for the medical treatment of cancer. The sphase marker bromodeoxyuridine was used as a surrogate of drug effect and administered 2 hours before tumor excision, whereas vessel position and perfusion were assessed via. This study was designed in accordance with the hypothesis that polymorphisms. Ck2 inhibitor cx4945 suppresses dna repair response. Preclinical in vitro and in vivo experiments were conducted to evaluate the hydrolysis and pharmacokinetics of ly2334737 and its downstream metabolites.
Division of hematologyoncology, college of medicine, university of florida, gainesville, florida, usa. Anderson h, lund b, bach f, thatcher n, walling j, hansen hh. Combined paclitaxel and gemcitabine as firstline treatment. Posterior reversible encephalopathy syndrome is a clinicoradiologic entity that may present with headaches, altered mental status, seizures and visual loss as well as specific neuroimaging findings. C, is a synthetic pyrimidine nucleoside analogue that has a structure similar to the naturally occurring nucleoside deoxycytidine. Irinotecan and gemcitabine have different mechanisms of action and their toxicity profiles do not overlap. Combination chemotherapy with gemcitabine plus oxaliplatin in. Gemcitabine is the firstline treatment for pancreatic adenocarcinoma, but is increasingly used to treat breast, bladder, and nonsmall cell lung cancers. Gemcitabineinduced reversible posterior leukoencephalopathy. Gemcitabine plus capecitabine compared with gemcitabine alone. Gemcitabine is a cytosine analogue and intravenously administered antineoplastic agent used in the therapy of several forms of advanced, pancreatic, lung, breast, ovarian and bladder cancer.
Following gemcitabine nucleotide incorporation into dna, only one additional nucleotide is added to the growing dna strand, followed by inhibition of further dna synthesis. Pancreatic ductal adenocarcinoma pdac, generally known as pancreatic cancer pc, ranks the fourth leading cause of cancerrelated deaths in the western world. Sep 21, 2016 its mechanism of action depends on phosphorylation and inhibition of the production of deoxynucleotide triphosphate required for normal dna synthesis. To examine the tumor microregional effects after gemcitabine administration to mice, we mapped the location of proliferating and hypoxic cells relative to vasculature in human colon cancer xenografts. An additional mechanism of action of gemcitabine is self. Raetz crh, chu my, srivastava sp, turcotte jg 1977 a. It is most commonly used in organ malignancies due to its functions in the promotion of cell death in several cancers including nonsmall cell lung cancer, colon squamous cell carcinoma, nasopharyngeal carcinoma and ovarian, breast and pancreatic cancer 25. High ribonucleotide reductase m1 rrm1 expression in resected lung cancers has been associated with better clinical outcomes. Singleagent activity of weekly gemcitabine in advanced nonsmall cell lung cancer. Preclinical and phase i data from 1997 described incidences of ventricular tachycardia in 1. Signaling dynamics of dna damage response invoked by. This action, termed masked chain termination, appears to lock the drug into.
Locally advanced pancreatic cancer mdedge hematology and. Gemcitabine transport in xenopus oocytes expressing. Metabolism, mechanisms of action, and selfpotentiation. When bacteria were introduced into tumors growing in mice, the tumors became resistant to gemcitabine, an effect that.
Several investigators have reported that the combination of irinitecan and gemcitabine displays modest activity as a secondline treatment for patients with advanced nsclc , 14. Does saturable formation of gemcitabine triphosphate occur. Alternatively, an amide prodrug of gemcitabine ly2334737 was discovered, which is able to avoid the extensive firstpass metabolism that occurs following administration of gemcitabine. Gemcitabine and oxaliplatin as neoadjuvant treatment for locally advanced, nonmetastasized pancreatic cancer. Promising molecular mechanisms responsible for gemcitabine. Gemcitabine is a nucleoside antimetabolite that inhibits dna synthesis. Polverino aj, patterson sd 1997 selective activation of caspases during apoptotic induction in hl60 cells. Population pharmacokinetics of gemcitabine and its metabolite. Combination chemotherapy with gemcitabine plus oxaliplatin. Pdf cellular pharmacology of gemcitabine researchgate.
Toxicity related to the cardiovascular system is rare. Patients with advanced or metastatic cancer refractory to standard therapy were eligible. We report a case of a 74yearold woman receiving adjuvant. National failure to operate on early stage pancreatic cancer. Gemcitabine is an anticancer drug used for a range of cancers, including nonsmall cell lung cancer nsclc, pancreatic cancer and breast cancer. Neoadjuvant chemoradiation with gemcitabine for locally. Extensive research has revealed a complex mechanism of action of this relatively new drug.
Dec 01, 2008 read does saturable formation of gemcitabine triphosphate occur in patients. Urachal cancer urc is a very rare but highly malignant tumor with an incidence of gemcitabine. It is a prodrug and, once transported into the cell, must be phosphorylated by deoxycytidine kinase to an active form. In this chapter, we summarize the role of the key enzymes in its metabolic activation and deactivation pathways. Gemcitabine and its hydrochloride are fluorinated deoxycytidine analogs with antitumor activity against solid tumors. It is known that gemcitabine has a unique mechanism of action known as selfpotentiation heinemann et al, 1992. Gemcitabine is another nucleoside analogue that acts as a very potent. Metastatic urachal cancer treated effectively with. Intracellular pharmacokinetics of gemcitabine, its.
The sphase marker bromodeoxyuridine was used as a surrogate of drug effect and administered 2 hours before tumor excision, whereas vessel position and perfusion were assessed via staining for. In masked chain termination, an additional physiologic nucleotide is incorporated prior to inhibition of dna polymerase, which conceals the incorporated gemcitabine nucleotide from. Potential role of intratumor bacteria in mediating tumor. Diffuse alveolar damage in a patient treated with gemcitabine. It is a prodrug and, once transported into the cell, must be. When bacteria were introduced into tumors growing in mice, the tumors became resistant to gemcitabine, an effect that was reversed.
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