MISCELLANEOUS
AGENTS
Hydroxyurea (Hydrea) inhibits the enzyme ribonu-cleotide reductase and thus
depletes intracellular pools of
deoxyribonucleotides, resulting in a specific impair-ment of DNA synthesis. The
drug therefore is an S-phase specific agent whose action results in an
accumu-lation of cells in the late G1- and early S-phases of the
cell cycle.
Hydroxyurea is rapidly
absorbed after oral adminis-tration, with peak plasma levels achieved
approxi-mately 1 to 2 hours after drug administration; its elimination
half-life is 2 to 3 hours. The primary route of ex-cretion is renal, with 30 to
40% of a dose excreted un-changed.
Hydroxyurea is used for the
rapid lowering of blood granulocyte counts in patients with chronic
granulocytic leukemia. The drug also can be used as maintenance therapy for
patients with the disease who have become resistant to busulfan. Only a small
percentage of pa-tients with other malignancies have had even brief re-missions
induced by hydroxyurea administration.
Hematological toxicity, with
white blood cells af-fected more than platelets, may occur. Megaloblastosis of
the bone marrow also may be observed. Recovery is rapid, generally within 10 to
14 days after discontinua-tion of the drug. Some skin reactions, including
hyper-pigmentation and hyperkeratosis, have been reported with chronic
treatment.
Procarbazine (Matulane) may autooxidize
sponta-neously, and during this reaction hydrogen peroxide and hydroxyl free
radicals are generated. These highly reactive products may degrade DNA and
serve as one mechanism of procarbazine-induced cytotoxicity. Cell toxicity also
may be the result of a transmethylation re-action that can occur between the N-methyl group of procarbazine and the
N7 position of guanine.
Procarbazine is rapidly
absorbed after oral adminis-tration and has a plasma half-life of only 10
minutes. The drug crosses the blood-brain barrier, reaching lev-els in CSF
equal to those obtained in plasma. Metabolism is extensive and complex. Urinary
excre-tion accounts for 70% of the procarbazine and its metabolites lost during
the first 24 hours after drug ad-ministration.
When originally tested as a
single agent in advanced Hodgkin’s disease, procarbazine produced tumor
re-gression responses that were brief, usually lasting only 1 to 3 months. The
combination of procarbazine with mechlorethamine, vincristine, and prednisone
in the MOPP regimen, however, resulted in an 81% complete remission rate in
Hodgkin’s disease. Most of these pa-tients are considered cured. Procarbazine
is also used in various combination chemotherapy protocols for non-Hodgkin’s
lymphomas and small cell anaplastic (oat cell) carcinoma of the lung. Limited
antitumor effects have been observed against multiple myeloma, melanoma, and
non–oat cell lung cancers.
The major side effects
associated with procarbazine therapy are nausea and vomiting, leukopenia, and
throm-bocytopenia. Skin rashes have been reported, as have rare cases of
allergic interstitial pneumonia. Procar-bazine administration produces a high
degree of chro-mosomal breakage, and the compound is mutagenic, ter-atogenic,
and carcinogenic in experimental systems.
Procarbazine may potentiate
the effects of tranquil-izers and hypnotics. Hypertensive episodes can result
if procarbazine is administered simultaneously with adrenomimetic drugs or with
tyramine-containing foods. Rarely, a reaction to alcohol similar to that
pro-voked by disulfiram may occur.
The observation that mitotane
(Lysodren) could pro-duce
adrenocortical necrosis in animals led to its use in the palliation of
inoperable adrenocortical adenocarci-nomas. A reduction in both tumor size and
adrenocorti-cal hormone secretion can be achieved in about half of the patients
taking the drug. Because normal adreno-cortical cells also are affected,
endogenous glucocorti-coid production should be monitored and replacement
therapy administered when appropriate.
Mitotane is incompletely
absorbed from the gas-trointestinal tract after oral administration. However,
once absorbed, it tends to accumulate in adipose tissue. Mitotane is slowly
excreted and will appear in the urine for several years. The major toxicities
associated with its use are anorexia, nausea, diarrhea, lethargy, somno-lence,
dizziness, and dermatitis.
Although both DNA and RNA
synthesis are inhibited in cells exposed to hexamethylmelamine (Hexalen), the molecular mechanisms of
these effects are not known.
Hexamethylmelamine is readily
absorbed after oral administration, with peak plasma levels achieved after 1
hour. The drug is readily metabolized to form a number of demethylated
metabolites. Urinary elimination is the primary route of drug excretion.
Hexamethylmelamine is useful
for the treatment of ovarian adenocarcinoma and is frequently combined with
cyclophosphamide, cisplatin, and doxorubicin in the treatment of this tumor. It
also has some activity against small cell lung cancer.
Nausea and vomiting are the
major toxicities associ-ated with hexamethylmelamine administration.
Myelo-suppression and a peripheral neuropathy also may occur.
Cisplatin (Platinol) is an inorganic coordination
com-plex with a broad range of antitumor activity. It is espe-cially useful in
the treatment of testicular and ovarian cancer. It binds to DNA at nucleophilic
sites, such as the N7 and O6 of guanine, producing alterations in DNA structure
and inhibition of DNA synthesis. Adjacent guanine residues on the same DNA
strand are preferen-tially cross-linked. This platinating activity is analogous
to the mode of action of alkylating agents. Cisplatin also binds extensively to
proteins. It does not appear to be phase specific in the cell cycle.
Cisplatin shows biphasic
plasma decay with a distri-bution phase half-life of 25 to 49 minutes and an
elimi-nation half-life of 2 to 4 days. More than 90% of the drug is bound to
plasma proteins, and binding may ap-proach 100% during prolonged infusion.
Cisplatin does not cross the blood-brain barrier. Excretion is predom-inantly
renal and is incomplete.
Cisplatin, combined with
bleomycin and vinblastine or etoposide, produces cures in most patients with
metastatic testicular cancer or germ cell cancer of the ovary. Cisplatin also
shows some activity against carci-nomas of the head and neck, bladder, cervix,
prostate, and lung.
Renal toxicity is the major
potential toxicity of cisplatin. Severe nausea and vomiting that often
accom-pany cisplatin administration may necessitate hospital-ization. Cisplatin
has mild bone marrow toxicity, yield-ing both leukopenia and thrombocytopenia.
Anemia is common and may require transfusions of red blood cells. Anaphylactic
allergic reactions have been de-scribed. Hearing loss in the high frequencies
(4000 Hz) may occur in 10 to 30% of patients. Other reported tox-icities
include peripheral neuropathies with paresthe-sias, leg weakness, and tremors.
Excessive urinary ex-cretion of magnesium also may occur.
Carboplatin (Paraplatin) is an analogue of cisplatin.
Its plasma half-life is 3 to 5 hours, and it has no significant protein
binding. Renal excretion is the major route of drug elimination.
Despite its lower chemical
reactivity, carboplatin has antitumor activity that is similar to that of
cisplatin against ovarian carcinomas, small cell lung cancers, and germ cell
cancers of the testis. Most tumors that are resistant to cisplatin are
cross-resistant to carbo-platin.
The major advantage of
carboplatin over cisplatin is a markedly reduced risk of toxicity to the
kidneys, pe-ripheral nerves, and hearing; additionally, it produces less nausea
and vomiting. It is, however, more myelo-suppressive than cisplatin. Other
adverse effects include anemia, abnormal liver function tests, and occasional
al-lergic reactions.
Mitoxantrone (Novantrone) is a synthetic anthraquinone
that is structurally and mechanistically related to the an-thracyclines. It
intercalates with DNA and produces sin-gle-strand DNA breakage. It is
cross-resistant with dox-
orubicin in multidrug-resistant
cells and in patients who have failed to respond to doxorubicin therapy.
Mitoxantrone is active
against breast carcinomas, leukemias, and lymphomas. Its antitumor efficacy in
pa-tients with breast cancer is slightly lower than that of doxorubicin. Its
major toxicity is myelosuppression; mu-cositis and diarrhea also may occur.
Mitoxantrone pro-duces less nausea, alopecia, and cardiac toxicity than does
doxorubicin.
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