<b>A More Advanced Temozolomide Discussion:</b>

Temozolomide, an oral imidazotetrazine second-generation alkylating agent, is the leading compound in a new class of chemotherapeutic agents that enter the cerebrospinal fluid and do not require hepatic metabolism for activation. 

In vitro, temozolomide has demonstrated antitumor activity against highly resistant malignancies. In clinical studies, temozolomide consistently demonstrates reproducible linear pharmacokinetics with approximately 100% p.o. bioavailability, noncumulative minimal myelosuppression that is rapidly reversible, and activity against a variety of solid tumors in both children and adults. 

Preclinical studies have evaluated the combination of temozolomide with other alkylating agents and inhibitors of the DNA repair protein O6-alkylguanine alkyltransferase to overcome resistance to chemotherapy in malignant glioma and malignant metastatic melanoma.

Temozolomide has recently been approved in the United States for the treatment of adult patients with refractory anaplastic astrocytoma and, in the European Union, for treatment of glioblastoma multiforme showing progression or recurrence after standard therapy.  These are brain tumors.

Predictable bioavailability and minimal toxicity make temozolomide a candidate for a wide range of clinical testing to evaluate the potential of combination treatments in different tumor types.

Temozolomide [TMZ] is an imidazotetrazine alkylating agent which undergoes spontaneous chemical conversion at physiological pH to the active species MTIC [5-(3-methyltriazene-1-yl)imidazole-4-carboxamide] which is stable at acid pH. Temozolomide was rapidly absorbed (mean time to peak concentration 1 h) and eliminated (mean half life = 1.8 h). Food produced a slight reduction (9%) in absorption of temozolomide. It is an oral cytotoxic agent with approximately 100% bioavailability after one administration.

Temozolomide administered as a single oral dose daily for 5 days every 4 weeks is well tolerated. Thrombocytopenia and neutropenia are the principal dose-limiting toxicities (DLTs) of TMZ . Prior myelosuppressive therapy is not a determinant of toxicity. The most common non-haematological toxicities were mild to moderate nausea and vomiting. TMZ doses should be individualized according to Body Surface Area, which is the most important factor influencing temozolomide clearance, rather than use of a prespecified oral dose for all individuals. Temozolomide 200 mg/m2/day for 5 days, every 28 days, was recommended for phase II studies.

MTIC methylates DNA at the O6 position of guanine, although this DNA damage may be repaired by the enzyme AGAT [O6-alkylguanine-DNA alkyltransferase], sometimes also known as AT or AGT or MGMT. The protein mediates a reaction with the O6-position of guanine in DNA, removing the lesion and leaving guanine intact. The mechanism of resistance to alkylating drugs such as temozolomide is thought to be due to the presence in tumor cells of this DNA repair protein. 
