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Cytotoxic Agents

Overview

Cytotoxic AgentsChemotherapy uses anticancer or “cytotoxic” drugs to destroy cancer cells by disrupting their growth. Cytarabine is commonly used in combination with interferon-a and in chemotherapy regimens to treat blastic-phase chronic myelogenous leukemia. The cytotoxic agents hydroxyurea and busulfan were the treatments of choice until interferon-a was introduced into the chronic myelogenous leukemia market twenty years ago. The older agents are less costly than interferon-a or imatinib and are orally administered.

Once chronic myelogenous leukemia enters the blastic phase, no treatment is particularly effective for controlling the disease. Clinicians use a wide variety of multidrug regimens that are based on the treatments for acute myelogenous leukemia and acute lym-phocytic leukemia. Commonly used cytotoxic agents are idarubicin (Pfizer’s Zavedos/Idamycin), daunorubicin (Sanofi-Aventis’s Cerubidin, Bedford’s Cerubidine, generics), and vincristine (Eli Lilly’s Oncovorin, generics).

Mechanism Of Action

Chemotherapeutic drugs work by damaging cancer cells as they undergo division, or mitosis, and preventing their further reproduction. Cells that are at rest (e.g., most normal cells) are much less vulnerable to chemotherapeutic damage. The cell cycle is composed of four distinct phases, G1, S, G2, and Go, during which the cell prepares for and undergoes mitosis. Combination chemotherapy includes drugs that damage cells at different stages in the process of cell division. Using more than one drug increases the chance of killing a greater number of cells. Chemotherapy also affects healthy body tissues that grow constantly (e.g., skin, hair, digestive system), a factor that explains the side effects, such as hair loss, suffered by patients.

Cytarabine

Cytotoxic AgentsIn the treatment of chronic-phase chronic myelogenous leukemia, cytarabine (Pfizer’s Cytosar-U, generics) is generally used in conjunction with interferon-a. The addition of cytarabine to interferon-a increases the toxicity of the treatment; whether the combination of the two therapies increases response rates is controversial.

Cytarabine is metabolized intracellularly into its active triphosphate form (cytosine arabinoside triphosphate). This metabolite then damages DNA via multiple mechanisms including the inhibition of alpha-DNA polymerase, inhibition of DNA repair through an effect on beta-DNA polymerase, and, most importantly, incorporation into DNA. Cytotoxicity is highly specific for the S phase of the cell cycle.

One study analyzed the efficacy of daily treatment with interferon-a (5 MU/m2) combined with LDAC (10 mg) (IFN+LDAC) in 140 patients with Ph-positive early chronic chronic myelogenous leukemia. Results were compared with those in patients receiving interferon-a with or without intermittent LDAC (seven days per month). CHRs were observed in 92% of patients treated with IFN+LDAC, and cytogenetic responses were observed in 74% (major in 50%, complete in 31%). The estimated four-year survival rate was 70%. The incidence of CHR was higher with IFN+LDAC than with intermittent or no LDAC (92% versus 84% versus 80%, respectively); similar results were noted for cytogenetic response (74% versus 73% versus 58%, respectively). Also, the time to achievement of a major cytogenetic response was significantly shorter than was obtained with previous interferon-a regimens.

Another study randomized 721 patients with Ph-positive, early chronic-phase chronic myelogenous leukemia to receive treatment with either hydroxyurea (50 mg/kg) and interferon-a (5 MU/m2/d) or hydroxyurea, interferon-a, and monthly courses of LDAC (20 mg/m2 for 10 days/month). The rate of CHR was 66% in the IFN+LDAC group versus 55% in the interferon-a/hydroxyurea group. The cytogenetic response rate was 66% in patients treated with LDAC (major in 41%, complete in 15%), which was significantly higher than the 52% response rate (major in 24%, complete in 9%) among patients treated with interferon-a/hydroxyurea. Patients in the IFN+LDAC group had a significantly better survival rate than patients in the interferon-a/hydroxyurea group: three-year survival rates were 86% versus 79%.

Cytarabine is generally administered as an intravenous preparation. An oral form of cytarabine is available in Japan.

Hydroxyured

Hydroxyurea (also known as hydroxycarbamide) (Bristol-Myers Squibb’s Hydrea, generics) effectively produces rapid hematologic responses and controls overall tumor burden in chronic myelogenous leukemia, as assessed by white blood cell count and spleen size. Although up to 80% of patients achieve hematologic remissions with hydroxyurea, cytogenetic responses are rare, and when they occur, are normally transient. Hydroxyurea is superior to busulfan, but inferior to interferon-a therapy, in terms of both survival rates (median survival 56 months with hydroxyurea and 44 months with busulfan) and toxicity. Hydroxyurea is also used to treat acute myeloid leukemia, head and neck cancers (before radiotherapy treatment), and ovarian cancer.

Hydroxyurea acts primarily as an inhibitor of ribonucleotide reductase. Inhibition of this protein leads to the depletion of essential DNA precursors. Another proposed mechanism of cytotoxicity involves direct chemical damage to DNA by hydroxyurea or a metabolite. Hydroxyurea also inhibits repair of DNA damaged by chemotherapy or radiation, offering potential synergy between hydroxyurea and radiation or alkylating agents. Laboratory studies suggest that hydroxyurea acts selectively against the episomes responsible for drug resistance. Hydroxyurea is specific for the S-phase of the cell cycle.

Because of its rapid onset of action, hydroxyurea can be used to reduce the leukemic burden in newly diagnosed patients before initiating interferon-a or progenitor stem-cell transplantation. Hydroxyurea is also used in patients with refractory disease or those who are intolerant of first-line therapy.

Common side effects associated with hydroxyurea are threefold. They include a temporary drop in bone marrow function, causing a fall in white blood cell count that increases the risk of severe infection; a drop in red cell count (anemia), causing fatigue and shortness of breath; and a drop in platelet numbers in the blood, causing bleeding or bruising.

Busulfan

Low-dose therapy with busulfan (GlaxoSmithKline’s Myleran) was once the mainstay of treatment for chronic myelogenous leukemia. The superior survival rates produced by imatinib, interferon-a, and hydroxyurea have reduced busulfan’s role to that of myeloablative therapy prior to allo-Stem-cell transplantation. This medication is also used to treat other disorders of the blood or bone marrow (e.g., myeloproliferative disorder, thrombocytosis, myelofibrosis).

Busulfan is a bifunctional alkylating agent that has been in clinical use since 1959. Carbonium ions rapidly form after systemic absorption of busulfan, leading to alkylation of DNA. This alkylation results in breaks in the DNA molecule as well as cross-linking of the twin strands, thus interfering with DNA replication and transcription of RNA. The antitumor activity of busulfan is cell cycle phase-nonspecific. Selective effects on granulocytopoesis are not well understood.

In the treatment of chronic myelogenous leukemia, busulfan is most commonly used in high doses as a myeloablative agent in patients receiving progenitor stem-cell transplantation. The dose of busulfan in this setting depends on the protocol, ranging from 8 to 16 mg/kg given over four days. The major dose-limiting effects of busulfan are myelotoxicity and pancytopenia. Myelotoxicity may be increased in patients who are recovering from the effects of prior chemotherapy or those who have received radioactive phosphorus or radiation to marrow-bearing bones.

Busulfan can lower the body’s ability to fight an infection, as well as prevent normal blood clotting. Other side effects associated with busulfan include hyperpigmentation, pulmonary toxicity, abnormal gonadal function, seizures, and veno-occlusive disease.

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