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

Docetaxel causes greater degrees of neutropenia than paclitaxel
but less peripheral neuropathy and asthenia and less frequent
hypersensitivity. Fluid retention is a progressive problem with multiple
cycles of docetaxel therapy, leading to peripheral edema, pleural
and peritoneal fluid, and pulmonary edema in extreme cases. Oral
dexamethasone, 8 mg/day, begun 1 day prior to drug infusion and
continuing for 3 days, greatly ameliorates fluid retention. In rare
cases, docetaxel may cause a progressive interstitial pneumonitis,
with respiratory failure supervening if the drug is not discontinued
(Read et al., 2002).
ESTRAMUSTINE
Estramustine (EMCYT) is a combination of estradiol coupled
to normustine (nornitrogen mustard) through a carbamate
link. Estramustine has weaker estrogenic and
antineoplastic activity than estradiol and other alkylating
agents. Although the intent of the combination was to
enhance the uptake of the alkylating agent into estradiolsensitive
prostate cancer cells, estramustine does not
function in vivo as an alkylating agent but rather binds to
β tubulin and microtubule-associated proteins, causing
microtubule disassembly and antimitotic actions.
Estramustine is used solely for the treatment of
metastatic or locally advanced hormone refractory
prostate cancer (Kitamura, 2001) at an initial dosage of
14 mg/kg/day in three or four divided doses.
Absorption, Fate, and Excretion. Following oral administration, at
least 75% of a dose of estramustine is absorbed from the GI tract
and rapidly dephosphorylated. Estramustine undergoes extensive
first-pass metabolism by CYP1A2 and CYP3A4 to an active oxidized
17-keto derivative, estramustine, and to multiple inactive products;
both active forms accumulate in the prostate. Some hydrolysis
of the carbamate linkage occurs in the liver, releasing estradiol,
estrone, and the normustine group. Estramustine and estromustine
have a plasma t 1/2
of 10 and 14 hours, respectively, and are excreted
as inactive metabolites, mainly in the feces (Bergenheim and
Henriksson, 1998). Estramustine inhibits the clearance of taxanes.
Clinical Toxicities. In addition to myelosuppression, estramustine
also possesses estrogenic side effects (gynecomastia, impotence, elevated
risk of thrombosis, and fluid retention), hypercalcemia, acute
attacks of porphyria, impaired glucose tolerance, and hypersensitivity
reactions, including angioedema.
EPOTHILONES
Microtubule-damaging compounds are limited by difficulties
in formulation, drug delivery, and susceptibility
to multidrug resistance. A new group of
microtubule-targeting drugs, the epothilones, overcomes
these problems in experimental systems. Several
epothilones currently are in various stages of clinical
development. Ixabepilone (IXEMPRA) is approved for
breast cancer treatment. Others in the pipeline include
the epothilone B analogs patupilone (EPO906) and
21-aminoepothilone B (BMS-310705), the epothilone D
analog KOS-1584 (R1645), and the synthetic sagopilone.
Chemistry. The epothilones are 16-membered polyketides discovered
as cytotoxic metabolites from a strain of Sorangium cellulosum,
a myxobacterium originally isolated from soil on the bank of
the Zambezi River in southern Africa (Gerth et al., 1996).
Six natural epothilones (A-F), and synthetic and semisynthetic
analogs are in various stages of development (Lee and Swain,
2008). Most trials of epothilones to date have evaluated compounds
of the subtypes A, B, and D, which differ in their functional groups
at carbon 12.
HO
H 3 C
H 3 C
O
H 3 C
CH 3
CH 3
OH
O
O
CH 3
CH 3
Initial studies of the natural epothilone compounds A, B, and
D showed good in vitro cytotoxic activity at nanomolar concentrations,
epothilone B having roughly twice the potency as epothilones
A and D (Lee and Swain, 2008). The early in vivo activity in animals,
however, was disappointing due to instability of their lactone ring.
Modification of epothilone B by substituting a nitrogen for the lactone
oxygen yielded ixabepilone, which is not susceptible to
esterases.
Mechanism of Action. The epothilones resemble taxanes in that they
bind to β tubulin and trigger microtubule nucleation at multiple sites
away from the centriole. This chaotic microtubule stabilization triggers
cell-cycle arrest at the G2-M interface and apoptosis. Epothilones bind
to a site distinct from that of taxanes. In colon cancer cell lines, p53
and Bax trigger apoptosis in ixabepilone-treated cells.
In vitro studies suggest that ixabepilone is less susceptible to
P-glycoprotein-mediated multidrug resistance when compared to
taxanes. Other mechanisms implicated in epothilone resistance
include mutation of the β-tubulin binding site and upregulation of
isoforms of β tubulin.
Absorption, Distribution, and Excretion. Ixabepilone is administered
intravenously. Because of its minimal aqueous solubility, it
is delivered in the solubilizing agent, polyoxyethylated castor
oil/ethanol (CREMOPHOR EL). CREMOPHOR has been implicated as
the cause of infusion reactions associated with paclitaxel and with
other drug formulations, but such reactions are infrequent when
administration is preceded by premedication with H 1
and H 2
antagonists.
The drug is cleared by hepatic CYPs and has a plasma t 1/2
of 52 hours.
Therapeutic Uses. In a phase III study for registration, patients with
metastatic breast cancer resistant to or pretreated with anthracyclines
and resistant to taxanes had an improved progression-free survival of
NH
IXABEPILONE
N
S
1709
CHAPTER 61
CYTOTOXIC AGENTS