DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

The precise sequence of events that leads from drug-induced
DNA damage to cell death has not been fully elucidated. In vitro,
camptothecin-induced DNA damage abolishes the activation of the
p34 cdc2 /cyclin B complex, leading to cell-cycle arrest at the G2 phase
(Tsao et al., 1993). Treatment with camptothecins can induce the
transcription of c-fos and c-jun early-response genes, and this occurs
in association with internucleosomal DNA fragmentation, a characteristic
of programmed cell death.
Mechanisms of Resistance. A variety of mechanisms of resistance to
topoisomerase I–targeted agents have been characterized in vitro,
although little is known about their significance in the clinical setting.
Decreased intracellular drug accumulation may underlie resistance in
cell lines. Topotecan, but not SN-38 or irinotecan, is a substrate for
P-glycoprotein. However, the clinical relevance of P-glycoproteinmediated
efflux as a mechanism of resistance against topotecan
remains unclear, as the magnitude of the effect in preclinical studies
was found to be substantially lower than that observed with other
MDR substrates, such as etoposide or doxorubicin. Other reports have
associated topotecan and irinotecan resistance with the MRP class of
transporters (Miyake et al., 1999). Cell lines that lack carboxylesterase
activity demonstrate resistance to irinotecan (Van Ark-Otte et al.,
1998), but in patients, the liver and red blood cells may have sufficient
carboxylesterase activity to convert irinotecan to SN-38. Camptothecin
resistance also may result from decreased expression or mutation of
topoisomerase I. Although a good correlation has been found in certain
tumor cell lines between sensitivity to camptothecin analogs and
topoisomerase I levels (Sugimoto et al., 1990), clinical studies have not
confirmed this association. Chromosomal deletions or hypermethylation
of the topoisomerase I gene are possible mechanisms of decreased
topoisomerase I expression in resistant cells. A transient downregulation
of topoisomerase I has been demonstrated following prolonged
exposure to camptothecins in vitro and in vivo. Mutations leading to
reduced topoisomerase I enzyme catalytic activity or DNA-binding
affinity have been associated with experimental camptothecin resistance
(Tamura et al., 1991). In addition, enzyme phosphorylation or
polyADP ribosylation may reduce the activity of topoisomerase I and
its susceptibility to inhibition. Finally, exposure of cells to topoisomerase
I–targeted agents upregulates topoisomerase II, an alternative
enzyme for DNA strand passage.
Very little is known about how the cell deals with the stabilized
DNA-topoisomerase complexes. Cellular repair processes may
not readily recognize the drug-enzyme-DNA complex. However, an
enzyme with specific tyrosyl-DNA phosphodiesterase activity may
be involved in the disassembly of topoisomerase I–DNA complexes
(Yang et al., 1996).
Absorption, Fate, and Excretion
Topotecan. Topotecan is approved for intravenous administration.
However, there has been interest in developing an oral dosage form
for the drug, which has a bioavailability of 30-40% in cancer
patients. Topotecan exhibits linear pharmacokinetics, and it is rapidly
eliminated from systemic circulation. The biological t 1/2
of total
topotecan, which ranges from 3.5-4.1 hours, is relatively short compared
to that of other camptothecins. Only 20-35% of the total drug
in plasma is found to be in the active lactone form. Within 24 hours,
30-40% of the administered dose appears in the urine. Doses should
be reduced in proportion to reductions in CrCl. Although several
oxidative metabolites have been identified, hepatic metabolism
appears to be a relatively minor route of drug elimination. Unlike
most other camptothecins considered for clinical development,
plasma protein binding of topotecan is low, at only 7-35%, which
may explain its relatively greater CNS penetration.
Irinotecan. The conversion of irinotecan to SN-38 is mediated predominantly
by carboxylesterases in the liver. Although SN-38 can
be measured in plasma shortly after beginning an intravenous infusion
of irinotecan, the AUC of SN-38 is only ~4% of the AUC of
irinotecan, suggesting that only a relatively small fraction of the dose
is ultimately converted to the active form of the drug. Irinotecan
exhibits linear pharmacokinetics at doses evaluated in cancer
patients. In comparison to topotecan, a relatively large fraction of
both irinotecan and SN-38 are present in plasma as the biologically
active intact lactone form. Another potential advantage of this analog
is that the t 1/2
of SN-38 is 11.5 hours, which is much longer than
the t 1/2
of topotecan. CSF penetration of SN-38 in humans has not
been characterized yet, although in rhesus monkeys, it is only 14%,
significantly lower than that observed for topotecan.
In contrast to topotecan, hepatic metabolism represents an
important route of elimination for both irinotecan and SN-38.
Oxidative metabolites have been identified in plasma, all of which
result from CYP3A-mediated reactions directed at the bispiperidine
side chain. These metabolites are not significantly converted to SN-
38. The total body clearance of irinotecan was found to be two times
greater in brain cancer patients taking antiseizure drugs that induce
hepatic CYPs, further attesting to the importance of oxidative
hepatic metabolism as a route of elimination for this drug (Gilbert
et al., 2003).
Glucuronidation of the hydroxyl group at position C10
(resulting from cleavage of the bispiperidine promoiety) produces
the only known metabolite of SN-38. Biliary excretion appears to
be the primary elimination route of irinotecan, SN-38, and their
metabolites, although urinary excretion also contributes significantly
(14-37%). Uridine diphosphate-glucuronosyltransferase 1A1
(UGT1A1), converts SN-38 to its inactive derivative (Iyer et al.,
1998). The extent of SN-38 glucuronidation inversely correlates with
the risk of severe diarrhea after irinotecan therapy. UGT1A1 also
glucuronidates bilirubin. Polymorphisms of this enzyme are associated
with familial hyperbilirubinemia syndromes such as Crigler-
Najjar syndrome and Gilbert syndrome. Crigler-Najjar syndrome is
rare (one in a million births), but Gilbert syndrome occurs in up to
15% of the general population and results in a mild hyperbilirubinemia
that may be clinically silent. The presence of UGT enzyme polymorphisms
may have a major impact on the clinical use of
irinotecan. A positive correlation has been found between baseline
serum unconjugated bilirubin concentration and both severity of neutropenia
and the AUC of irinotecan and SN-38 in patients treated
with irinotecan. Moreover, severe irinotecan toxicity has been
observed in cancer patients with Gilbert syndrome, presumably due
to decreased glucuronidation of SN-38. The presence of bacterial
glucuronidase in the intestinal lumen potentially can contribute to
irinotecan’s GI toxicity by releasing unconjugated SN-38 from the
inactive glucuronide metabolite excreted in the bile.
Therapeutic Uses
Topotecan. Topotecan (HYCAMTIN) is indicated for previously treated
patients with ovarian and small cell lung cancer. Its significant hematological
toxicity has limited its use in combination with other active
agents in these diseases (e.g., cisplatin).
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CHAPTER 61
CYTOTOXIC AGENTS