Medical Pharmacology Chapter 33-34: Anticancer Drugs
Cytidine Analogues: Gemcitabine (Gemzar)
Gemcitabine (Gemsar) is a difluoro derivative of deoxycytidine.
Gemcitabine exhibit similarity in metabolism, structure and mechanism of action to cytarabine (ara-C).6
However, antitumor effects associate was cytarabine administration appear broader.
Gemcitabine exhibits activity against some human solid tumors such as pancreatic, bile duct, gallbladder, small and non-small-cell lung cancer, bladder, ovarian, and breast cancer.
Some hematological malignancies are also susceptible to gemcitabine treatment including Hodgkin's and non-Hodgkin's lymphoma.6
Primary antineoplastic uses of this drug include:1
Metastatic pancreatic cancer
Non-squamous, non-small cell lung cancer
Ovarian cancer and
Activation of gemcitabine is a several step process3
Initially a monophosphate derivative is formed, catalyzed by deoxycytidine kinase.
Diphosphate in triphosphate nucleotide species are formed with the aid of nucleoside kinases.
Antitumor effects may involve several different mechanisms including:
Ribonucleotide reductase enzyme inhibition by gemcitabine diphosphate, resulting in decreased levels of deoxyribonucleoside triphosphates needed for DNA synthesis.
Gemcitabine-triphosphate mediated DNA polymerase α and DNA polymerase β inhibition inducing inhibition of both DNA synthesis and repair.
Incorporation into DNA of gemcitabine triphosphate causing inhibition of DNA synthesis and impaired function.3
Gemcitabine enter cells primarily utilizing the ENT1 transporter. in addition, the CNT1 transporter and a nucleoside base transporter (malignant mesothelioma cells) are also involved.
ENT1 is a sodium-independent purine and pyrimidine nucleoside transporter.
Nucleoside transporters are subdivided into two classes:
Equilibrative bi-directional facilitators (ENTs) and
Na+ -dependent concentrative transporters (CNTs).
ENT1 has been described as a glycosylated protein with 456 amino acid residues (50 kDa)
ENTs are proposed to consist of 11-transmembrane helix topology.
ENT1 is a widely distributed transporter, present in erythrocytes, liver, heart, spleen, lung, kidney, intestine and brain.
ENT1 is also expressed and functional in mitochondrial membrane.
Given its tissue distribution, this transporter likely plays an important role in nucleoside provision either derived from diet or produced by tissues, as well as for salvage pathways of nucleotide synthesis and in those cells they do not exhibit de novo synthesis pathways.
ENT1 is thought involved in absorption, distribution and xenobiotic excretion.
Clinically, ENT1 is important in describing nucleoside analog drug disposition10 .
These drugs are part of treatment protocols for cancer, cardiovascular disease, viral and parasitic infections and in certain neurological pathologies.
The drugs in question act following nucleic acid incorporation and typically interfere with nucleic acid synthesis or interfere with physiological nucleoside metabolism.
The first nucleoside analog approved for cancer therapy was the pyrimidine analog cytarabine (ara-C).
This drug is primarily dependent on ENT1 for cell entry.
ENT1 appears responsible for the transport of a number of anticancer drugs into the cell.
These drugs include:
Cytotoxic actions of gemcitabine, by contrast to cytarabine, is not dependent solely on action during the S-phase of the cell-cycle.1
dFdCTP (gemcitabine triphosphate) is a competitive inhibitor with dCTP, weakly inhibiting DNA polymerase.1
dFdCTP (gemcitabine triphosphate), however, dFdCTP is an effective ribonucleotide reductase inhibitor (RNR a.k.a. ribonucleoside diphosphate reductase, rNDP)11 leading to a decrease in deoxyribonucleotide pools.
RNR catalyzes conversion of deoxyribonucleotides from ribonucleotides.11,12
RNR is an iron -dependent enzyme necessary for DNA synthesis.
The active form, a heterotrimeric tetramer, is formed from a large RNR1 in smaller RNR2 subunits (class I RNR).11
Adequate Deoxyribonucleotide pools are a requirement for DNA synthesis.
dFdCTP (gemcitabine triphosphate) incorporation into DNA results in DNA strand termination, an effect not amenable to repair.
Incorporation of dFdCTP is required for gemcitabine-induced programmed cell death (apoptosis).
Inactivation of gemcitabine is catalyzed by cytidine deaminase localized not only in tumor cells but in the body generally.1
Gemcitabine route of administration is by intravenous infusion.
The primary factor describing the pharmacokinetics of gemcitabine is liver-plasma and other organ deamination rates.
The major urinary elimination metabolite is dFdU.
About 90% of metabolized drug is recovered in urine.6
In the presence of notable renal insufficiency or dysfunction gemcitabine metabolites, dFdU and the triphosphate form may become elevated to toxic levels.
The parent compound, gemcitabine, exhibits a short plasma half-life (t1/2 about 15 minutes).
Drug clearance appears gender and age dependent in women and older individuals.
Patients in these groups exhibit extended elimination times.
Plasma clearance is about 30% lower in women and in elderly individuals.6
Resistance to the antineoplastic effects of gemcitabine may occur by various mechanisms.6
As noted, gemcitabine requires transport to enter cells where it can be transformed to its active, cytotoxic form.
This transport is primarily dependent on the ENT1 (human equilibrative nucleoside transporter 1).
Accordingly, gemcitabine resistance is associated with reduced ENT1 protein expression.
Furthermore, inhibitors of ENT1 are associated with gemcitabine resistance.
Gemcitabine requires activation to phosphorylated forms in order that its antineoplastic activities are realized.
Cellular drug resistance may be associated with decrease in deoxycytidine kinase (dCK) enzyme expression or reduced enzyme activity.
Enhanced activity (or expression) of degradative enzymes cytidine deaminase and dCMP deaminase (deoxycytidylate deaminase) is also associated with gemcitabine resistance.6
In terms of a specific clinical circumstance, some CD44-positive pancreatic cancer stem cells exhibit resistance to gemcitabine treatment.
Gemcitabine in the monotherapy setting appears relatively well-tolerated.6
The principal dose-limiting toxic reaction is myelosuppression.
Neutropenia appears to occur more frequently than thrombocytopenia.
Increased likelihood of hematological toxicity appears correlated with longer infusions.
About half of patients while undergoing gemcitabine treatment experience flu -like symptoms, such as fever and myalgias,
toxicities are very uncommon but may include hemolytic-uremic syndrome and
thrombotic thrombocytopenic purpura (renal microangiopathy syndromes).6