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

Natural Products in Cancer
Chemotherapy: Hormones and
Related Agents
Beverly Moy, Richard J. Lee,
and Matthew Smith
The growth of a number of cancers is hormone dependent
or regulated by hormones. Research in the fields of
fertility, birth control, and menopause has yielded valuable
hormone analogs and antagonists for the treatment
of both breast and prostate cancer. These molecules interrupt
the stimulatory axis created by systemic pools of
androgens and estrogens, inhibit hormone production or
binding to receptors, and ultimately block the complex
expression of genes that promotes tumor growth and survival.
These drugs have proven effective in extending
survival and delaying or preventing tumor recurrence in
breast cancer and prostate cancer.
GLUCOCORTICOIDS
The pharmacology, major therapeutic uses, and toxic
effects of the glucocorticoids are discussed in Chapter 42.
Only the applications of these drugs in the treatment of
neoplastic disease are considered here. Glucocorticoids
act through their binding to a specific physiological
receptor that translocates to the nucleus and induces
anti-proliferative and apoptotic responses in sensitive
cells. Because of their lympholytic effects and their ability
to suppress mitosis in lymphocytes, glucocorticoids
are used as cytotoxic agents in the treatment of acute
leukemia in children and malignant lymphoma in children
and adults.
In acute lymphoblastic or undifferentiated leukemia of childhood,
glucocorticoids may produce prompt clinical improvement and
objective hematological remissions in ≤30% of children. Although
these responses frequently are characterized by complete disappearance
of all detectable leukemic cells from the peripheral blood and bone
marrow, the duration of remission is brief. Remissions occur more rapidly
with glucocorticoids than with antimetabolites, and there is no
evidence of cross-resistance to unrelated agents. For these reasons, therapy
is initiated with prednisone and vincristine, often followed by an
anthracycline or methotrexate, and L-asparaginase. Glucocorticoids are
a valuable component of curative regimens for other lymphoid malignancies,
including Hodgkin’s disease, non-Hodgkin’s lymphoma,
multiple myeloma, and chronic lymphocytic leukemia (CLL).
Glucocorticoids are extremely helpful in controlling auto-immune
hemolytic anemia and thrombocytopenia associated with CLL.
The glucocorticoids, particularly dexamethasone, are used in
conjunction with radiotherapy to reduce edema related to tumors in
critical areas such as the superior mediastinum, brain, and spinal cord.
Doses of 4-6 mg every 6 hours have dramatic effects in restoring neurological
function in patients with cerebral metastases, but these
effects are temporary. Acute changes in dexamethasone dosage can
lead to a rapid recrudescence of symptoms. Dexamethasone should
not be discontinued abruptly in patients receiving radiotherapy or
chemotherapy for brain metastases. Gradual tapering of the dosage
may be undertaken if a clinical response to definitive antitumor therapy
has been achieved. The antitumor effects of glucocorticoids are
mediated by their binding to the glucocorticoid receptor, which activates
a program of gene expression that leads to apoptosis.
Several glucocorticoids are available and at equivalent
dosages exert similar effects (see Chapter 42). Prednisone, e.g., usually
is administered orally in doses as high as 60-100 mg, or even
higher, for the first few days and gradually reduced to levels of
20-40 mg/day. A continuous attempt should be made to establish the
lowest possible dosage required to control the manifestations of the
disease. These agents, when used chronically, exert a wide range of
side effects, including glucose intolerance, immunosuppression,
osteoporosis, and psychosis (see Chapter 42). Dexamethasone is the
preferred agent for remission induction in multiple myeloma, usually
in combination with melphalan, anthracyclines, vincristine, bortezomib,
or thalidomide.
PROGESTINS
Progestational agents (see Chapters 40 and 66) have been
used as second-line hormonal therapy for metastatic