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

1744
O
HO
cell
membrane
IGF1R
Other TK receptors
PI3K
stress
energy depletion
amino acid status
Ras
SECTION VIII
O
HO
N
O
O O
O O
O
O
OH
O
Rapamycins
FKBP12
Akt
mTORC1
mTORC2
MAPK
CHEMOTHERAPY OF NEOPLASTIC DISEASES
RAPAMYCIN (SIROLIMUS)
Mechanisms of Action and Resistance. The rapamycins inhibit an
enzyme complex, mTORC1, which occupies a downstream position
in the PI3 kinase pathway (Figure 62–4). mTOR forms the mTORC1
complex with a member of the FK506-binding protein family,
FKBP12. Among other actions, mTORC1 phosphorylates S6 kinase
and also relieves the inhibitory effect of 4EBP on initiation factor elf-
4E, therby promoting protein synthesis and metabolism. The antitumor
actions of the rapamycins result from their binding to FKBP12
and inhibition of mTORC1. Rapamycin and its congeners have
immunosuppressant effects, inhibit cell-cycle progression and angiogenesis,
and promote apoptosis.
Resistance to mTOR inhibitors is incompletely understood
but may arise through the action of a second mTOR complex,
mTORC2, which is unaffected by rapamycins and which regulates
AKT kinase. Experimental work suggests that inhibition of
mTORC1 leads to mTORC2 activation of AKT kinase and the MAP
kinase pathway, and these actions may be responsible for incomplete
responses or resistance of rapamycins (Carracedo et al., 2008). Dual
mTORC1 and mTORC2 inhibitors are in clinical development.
S6K1
translation
autophagy
4EBP
translation
metabolism
proliferation
survival
proliferation
metabolism
Figure 62–4. Insulin-like growth factor 1 receptor (IGF-1R) and
other tyrosine kinase (TK) growth factor receptors signal through
multiple pathways. A key pathway is regulated by phosphatidylinositol-3
kinase (PI3K) and its downstream partner, the mammalian
target of rapamycin (mTOR). Rapamycins complex with
FKBPP12 to inhibit the mTORC1 complex. mTORC2 remains
unaffected and responds by upregulating Akt, driving signals
through the inhibited mTORC1. The various downstream outputs
of the two complexes are shown. Phosphorylation of 4EBP
by mTOR inhibits the capacity of 4EBP to inhibit eif-4E and
slow metabolism. 4EBP, eukaryotic initiation factor 4e (eif-4E)
binding protein; S6K1, S6 kinase 1; FKBP12, the immunophilin
target (binding protein) for tacrolimus (FK506).
Absorption, Fate, and Excretion. The FDA has approved both temsirolimus
and everolimus for treatment of renal cancer. Temsirolimus
prolongs survival and delays disease progression in patients with
advanced and poor- or intermediate-risk renal cancer, as compared
to standard interferon-α treatment. Everolimus, as compared to
placebo, prolongs survival in patients who had failed initial treatment
with anti-angiogenic drugs (Motzer et al., 2008). mTOR
inhibitors also have antitumor activity against mantle cell lymphomas
(Ansell et al., 2008) and are under active investigation in
combination with hormonal therapies, EGFR inhibitors, and cytotoxic
drugs.
For renal-cell cancer, temsirolimus is given in weekly doses
of 25 mg, intravenously, while everolimus is administered orally
in doses of 10 mg daily. Both drugs should be administered in the
fasting state at least 1 hour before a meal. Both parent molecules
are metabolized by CYP3A4. Temsirolimus has a plasma t 1/2
of
30 hours; its primary metabolite, sirolimus, has a longer t 1/2
of
53 hours. Because sirolimus has equivalent activity as an inhibitor
of mTORC1, and has a greater AUC, sirolimus is likely the more
important contributor to antitumor action in patients (Hutson
et al., 2008). Everolimus has a plasma t 1/2
of 30 hours, and on a
weekly schedule at doses of 20 mg, it maintains inhibition of
mTORC1 for 7 days in white blood cells (O’Donnell et al., 2008).
At their usual clinical doses, both agents provide peak drug levels
of ~1 μM.
Both drugs are susceptible to interactions with other agents
that affect CYP3A4 activity. Ketoconazole, a CYP3A4 inhibitor,
causes a 2- to 3-fold increase in the AUCs of both temsirolimus and
sirolimus, while inducers of metabolism such as rifampin or phenytoin
can decrease the C Pmax
of temsirolimus by 36% and decrease
the AUC of its metabolite by >50%. The dose of temsirolimus
should be doubled in the presence of inducers and reduced by half
in the presence of ketoconazole (Hutson et al., 2008). Hepatic dysfunction
delays drug clearance; for everolimus, the dose should be