Medical Pharmacology Chapter 33-34: Anticancer Drugs
Alkylating Agents (Continued)
Temozolomide (Temodar) is a monofunctional alkylating agent and as such cannot cross-link DNA but rather alkylates, explaining its cytotoxic activity.8
Temozolomide is considered a "prodrug" given that it must be converted, nonenzymatically, to the active alkylating metabolite, methyl-triazene-1-yl)-imidazole-4-carboxamide (MTIC).
The specific alkylation reaction involves methylation of DNA at the O6, N7 guanine positions.
Modification at these sites promote DNA double strand breakage. Furthermore, this damage induces "programmed cell death" a.k.a. apoptosis.8
Temozolomide is administered orally usually for the treatment of glioblastoma multiforme or for cases of anaplastic astrocytoma in individuals not responding to procarbazine or nitrosourea anticancer agents.2
Absorption, Distribution, Metabolism, Excretion:
Temozolomide is well absorbed following oral administration.8
Absorption is complete and rapid.
Temozolomide as the parent compound has a volume of distribution (Vd) of about 0.4 L/kg.
The drug readily penetrates the blood brain barrier with CSF levels approximating 37% of plasma levels.
Temozolomide only binds to proteins moderately (15%).
The active alkylating agent MTIC is eliminated as CO2 and as 5-aminoimidazole-4-carboxamide (AIC) in the urine.8
Cytochrome P450 enzymes, the microsomal drug metabolizing enzymes, do not contribute substantially to temozolomide metabolism with less than 6% of the agent excreted in the urine unchanged.2
Women seem to clear the drug less effectively compared to men which may explain a higher risk for severe neutropenia and thrombocytopenia in females, at least during the initial treatment cycle.2
Resistance to the antineoplastic effects of temozolomide is due to enzyme catalyzed reversal of methylated DNA bases.2
The enzyme involved is O6-methylguanine-DNA methyltransferase.2
Unless the promoter for the gene encoding this enzyme is defective, the enzyme is sufficient to block or very significantly limit the clinical efficacy of temozolomide.9
Some Clinical Uses:
Temozolomide along with radiation therapy represents the standard agent for patients with malignant glioma and astrocytoma.1
With respect to treating glioblastoma multiforme, efficacy of temozolomide is usually substantially compromised by the enzyme O6-methylguanine-DNA methyltransferase which removes (detoxifies) the methylguanine residues which represent the basis for temozolomide cytotoxic action.9
Temozolomide is active in all phases of the cell cycle with substantial enhanced activity in those tumors that do not express active MGMT (O6-methylguanine-DNA methyltransferase).1
Adverse Effects of Alkylating Antineoplastic Drugs Generally:1
Alkylating antineoplastic drugs have a variety of side effects and most of these agents exhibit a similar pattern.1
Dose-limiting toxicities are associated with most alkylating drugs with respect to bone marrow cells and the somewhat of a lesser degree to intestinal mucosa.1
Most of the agents, examples including melphalan, cyclophosphamide, ifosfamide and chlorambucil, induce myelosuppression which is more profound in the time frame of 1-2 weeks with recovery from 2 to 3 weeks.1
Cyclophosphamide, compared other drugs in this category, has reduced effects on peripheral blood platelet levels.
Busulfan, by contrast, reduces levels of all blood components especially stem cells and furthermore myelosuppression so induced is unusually long (months to years).
Carmustine and similar drugs induce both delayed and prolonged reduction in platelet and granulocyte levels.
Alkylating drugs exhibit significant cytotoxicity with respect to hair follicles and rapidly dividing mucosal cells.1
The clinical effects may be profound in that oral mucosal ulceration and similar intestinal effects may be both painful and may result in aberrant electrolyte levels.
Alopecia (hair loss) may commonly develop.
Mucosal effects are especially pronounced in high-dose alkylating agent chemotherapy protocols associated with bone marrow transplantation.1
G.I. mucosal effects in this instance may render the patient more susceptible to bacterial sepsis from the G.I. tract.
For this application, some alkylating agents may be preferable insofar as producing less mucosal damage; examples include melphalan, cyclophosphamide and thiotepa.
Nausea and vomiting (nervous system effects) are frequently observed following carmustine administration.1
Ifosfamide has been identified as the most neurotoxic of the alkylating drugs, producing changed mental status, generalized seizure, cerebellar ataxia and coma.
At higher doses, busulfan is seizurogenic.
Temozolomide as well as other alkylating drugs may cause pulmonary fibrosis, appearing as a delayed response months after treatment.1
Hepatic veno-occulsive disease following carmustine or busulfan may occur as a result of vascular endothelial pathologies.1
Such veno-occulsive disease (VOD) can be reversed by defibrotide, an oligonucleotide mixture which is pro-fibrolytic.
Cyclophosphamide/ifosfamide metabolism results in acrolein which is both nephrotoxic and urotoxic and can cause serious hemorrhagic cystitis (high-dose regimens).
Very unstable alkylating drugs such as mechlorethamine and nitrosoureas-type drugs exhibit vein-damaging vesicant properties.1
Extravasation can result in ulceration.
Alkylating drug administration is associated with risk of inducing leukemia.1
Acute nonlymphocytic leukemia due to treatment has been associated with particular mutations (e.g. p53) and chromosomal changes (chromosome 5 or 7).
Such leukemic response may follow an initial neutropenia or anemia and may exhibit bone marrow morphologies suggestive of myelodysplasia.
Certain alkylating agents are more likely to cause leukemia; these agents include melphalan, nitrosoureas and procarbazine.
Adverse Effects of Temozolomide:8
Some examples of adverse reactions, occurring with the frequency of >10%, associated with temozolomide include:
Cardiovascular: peripheral edema; CNS: fatigue, headache, seizure, dizziness, hemiparesis, ataxia
Dermatologic: alopecia (>50%), skin rash
Gastrointestinal: nausea (>50%), vomiting, constipation, anorexia, diarrhea
Hematologic and Oncologic: lymphocytopenia, thrombocytopenia, neutropenia, leukopenia
Infection: viral infection
Neuromuscular and skeletal: weakness