Page 974 - Basic _ Clinical Pharmacology ( PDFDrive )

960 SECTION VIII Chemotherapeutic Drugs

trifluridine, which can then be activated to the active metabolite Gemcitabine
forms. The advantages of TAS-102 are that it retains clinical activ-
ity in 5-FU resistant tumors and it displays similar clinical activity Gemcitabine is a fluorine-substituted deoxycytidine analog that is
in the setting of wild-type and mutant RAS colorectal cancer. The phosphorylated initially by the enzyme deoxycytidine kinase to the
main dose-limiting toxicity is myelosuppression, with neutropenia monophosphate form and then by other nucleoside kinases to the
more commonly observed than anemia and thrombocytopenia. diphosphate and triphosphate nucleotide forms. The antitumor
The other adverse effects commonly observed with this oral fluo- effect is considered to result from several mechanisms: inhibition
ropyrimidine are GI toxicity with diarrhea and nausea/vomiting, of ribonucleotide reductase by gemcitabine diphosphate, which
fatigue, and anorexia. reduces the level of deoxyribonucleoside triphosphates required
for DNA synthesis; inhibition by gemcitabine triphosphate of
DNA polymerase-α and DNA polymerase-β, thereby resulting in
DEOXYCYTIDINE ANALOGS blockade of DNA synthesis and DNA repair; and incorporation
of gemcitabine triphosphate into DNA, leading to inhibition of
Cytarabine DNA synthesis and function.
Cytarabine (ara-C) is an S phase–specific antimetabolite that NH 2
is converted by deoxycytidine kinase to the 5′-mononucleotide
(ara-CMP). Ara-CMP is further metabolized to the diphosphate N
and triphosphate metabolites, and the ara-CTP triphosphate is
thought to be the main cytotoxic metabolite. Ara-CTP com- O N
petitively inhibits DNA polymerase-α and DNA polymerase-β, HOCH 2 O
thereby resulting in blockade of DNA synthesis and DNA repair, F
respectively. This metabolite is also incorporated into RNA and
DNA. Incorporation into DNA leads to interference with chain OH F
elongation and defective ligation of fragments of newly synthe-
sized DNA. The cellular retention of ara-CTP appears to correlate Gemcitabine
with its lethality to malignant cells.
In contrast to cytarabine, which has no activity in solid tumors,
gemcitabine has broad-spectrum activity against both solid tumors
and hematologic malignancies. In fact, this nucleoside analog was
NH 2 NH 2
initially approved for use in advanced pancreatic cancer and is
N N
now widely used to treat a broad range of malignancies, including
NSCLC, bladder cancer, ovarian cancer, soft tissue sarcoma, and
O O
N N non-Hodgkin’s lymphoma. Myelosuppression in the form of neu-
HOCH 2 O HOCH 2 O tropenia is the principal dose-limiting toxicity. Nausea and vomit-
ing occur in 70% of patients, and a flu-like syndrome has also
HO
been observed. In rare cases, renal microangiopathy syndromes,
including hemolytic-uremic syndrome (HUS) and thrombotic
HO HO
thrombocytopenic purpura (TTP), have been reported.
Cytosine Cytosine
deoxyriboside arabinoside
(cytarabine)
PURINE ANTAGONISTS
After intravenous administration, the drug is cleared rap- 6-Thiopurines
idly, with most of an administered dose being deaminated to
inactive forms. The stoichiometric balance between the level of 6-Mercaptopurine (6-MP) was the first of the thiopurine analogs
activation and catabolism of cytarabine is important in deter- found to have clinical efficacy in cancer therapy. This agent is
mining its eventual cytotoxicity. The clinical activity of cyta- used primarily in the treatment of childhood acute leukemia, and
rabine is highly schedule-dependent and, because of its rapid a closely related analog, azathioprine, is used as an immunosup-
degradation, it is usually administered via continuous infusion pressive agent (see Chapter 55). As with other thiopurines, 6-MP
over a 5- to 7-day period. Its activity is limited exclusively to is inactive in its parent form and must be metabolized by hypo-
hematologic malignancies, including acute myelogenous leuke- xanthine-guanine phosphoribosyl transferase (HGPRT) to form
mia and non-Hodgkin’s lymphoma. This agent has absolutely the monophosphate nucleotide 6-thioinosinic acid, which in turn,
no activity in solid tumors. The main adverse effects associated inhibits several enzymes of de novo purine nucleotide synthesis
with cytarabine therapy include myelosuppression, mucosi- (Figure 54–6). The monophosphate form is eventually metabolized
tis, nausea and vomiting, and neurotoxicity when high-dose to the triphosphate form, which can then be incorporated into
therapy is administered. both RNA and DNA. Significant levels of thioguanylic acid and