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

1750 good performance status and normal renal and hepatic function
before beginning therapy and should be closely supervised during
drug administration.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Denileukin Diftitox. Denileukin diftitox (ONTAK) is an
immunotoxin made from the genetic recombination of
IL-2 and the catalytically active fragment of diphtheria
toxin (Foss et al., 2001). The limited tissue expression
of the high-affinity IL-2R makes this an attractive
target for an immunotoxin, as cells that do not express
the IL-2R or express only the intermediate- or lowaffinity
receptor types are significantly less sensitive
to this agent. Introduction of the diphtheria toxin fragment
into cells leads to ADP-ribosylation and inactivation
of eukaryotic elongation factor EF-2, inhibition
of protein synthesis, and thence, cell death.
Denileukin diftitox is FDA-approved for the treatment of
recurrent/refractory cutaneous T-cell lymphomas. It should be
administered at 9 or 18 μg/kg/day by intravenous infusion over
30-60 minutes for 5 consecutive days every 21 days for eight cycles.
Response rates of 30-37% have been achieved in such patients with
denileukin diftitox, with a median response duration of 6.9 months
(Olsen et al., 2001). Additional patients derived clinical benefit but
did not meet the objective criteria for response. The systemic exposure
to denileukin diftitox is variable but proportional to dose. The
drug has a distribution t 1/2
of 2-5 minutes with a terminal t 1/2
of
~70 minutes. Immunological reactivity to denileukin diftitox can be
detected in virtually all patients after treatment but does not preclude
clinical benefit with continued treatment. Denileukin diftitox clearance
in later cycles of treatment accelerates by 2- to 3-fold as a result
of development of antibodies, but serum levels exceed those required
to produce cell death in IL-2R-expressing cell lines (1-10 ng/mL for
>90 minutes). Patients with a history of hypersensitivity reactions
to diphtheria toxin or IL-2 should not be treated. Significant toxicities
associated with denileukin diftitox typically are acute hypersensitivity
reactions, a vascular leak syndrome, and constitutional
toxicities; glucocorticoid premedication significantly decreases toxicity
(Foss et al., 2001).
Colony-Stimulating Factors
As noted in the preceding sections, many agents used
for cancer chemotherapy suppress the production of
multiple types of hematopoietic cells, and bone marrow
suppression often has limited the delivery of
chemotherapy on schedule and at prescribed doses. The
availability of recombinant growth factors for erythrocytes
(i.e., erythropoietin), granulocytes (i.e., G-CSF),
and granulocytes and macrophages (i.e., GM-CSF)
have advanced the ability to use combination therapy
or high-dose therapy with diminished complications
such as febrile neutropenia. The individual growth factors
and specifics of supportive use of these agents are
described in detail in Chapter 37.
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