Cytarabine toxicity

P-D-Arabinofuranosylcytosine [147-94-4] (ara-C, 16), C H N O, reportedly has had significant therapeutic effects in patients with localized herpes zoster, herpes eye infections, and herpes encephaUtis (33), although several negative results have also been reported (34) (Fig. 2). Ara-C, also known as cytarabine, is quite toxic and is only recommended for very severe viral infections. It is rapidly deaminated in humans to the relatively inactive ara-U Ara-C is converted in the cell to the 5 -monophosphate by deoxycytidine kinase, followed by formation of the corresponding di- and triphosphate. The triphosphate has been shown to inhibit DNA polymerase. 

Cytarabine is used in the chemotherapy of acute myelogenous leukemia, usually in combination with anthracyclines, thioguanine, or both. It is less useful in acute lymphoblastic leukemia and lymphomas and has marginal activity against other tumors. Myelosuppres-sion is a major toxicity, as is severe bone marrow hypoplasia nausea and mucositis may also occur. 

Prior to the introduction of imatinib, the combination of interferon-alfa and low dose cytarabine was the nontransplant treatment of choice for patients in chronic phase CML. The precise mechanism of action of interferon-alfa remains unknown. The addition of cytarabine to interferon-alfa improves the response compared with interferon alone. This combination produces cytogenetic response rates of 30%, much lower than imatinib.13 One of the major drawbacks, in addition to the low response rates, is interferon s toxicity,... 

Cytarabine—high doses can cause CNS toxicity (cerebellar dysfunction) neurotoxicity increases as infusion time increases... 

BFM and St. Jude protocols, are that on BFM protocols no topoisomerase 11 inhibitors are given in close association with thiopurines and, finally, that on BFM protocols no intrathecal triple therapy (methotrexate, cytarabine, and a glucocorticoid) are given concurrent with cranial radiotherapy and 6-MP. Another important toxicity issue associated with TPMT status relates to the above-described VOD-like symptoms of the liver in childhood ALL patients treated with 6-TG on the British MRC ALL97 trial (209). In this trial, TPMT activity was significantly lower in children in whom VOD developed while no differences in RBC 6-TGN levels were described. This information in association with ongoing research efforts will help to develop a better understanding of 6-TG-associated liver toxicity and may help to identify those individuals upfront who should not be administered 6-TG. 

Hensley ML, Peterson B, Silver RT, Larson RA, Schiffer CA, Szatrowski TP. Risk factors for severe neuropsychiatric toxicity in patients receiving interferon alfa-2b and low-dose cytarabine for chronic myelogenous leukemia analysis of Cancer and Leukemia Group B 9013. J Clin Oncol 2000 18(6) 1301-8. 

CYTARABINE FLUDARABINE T efficacy of cytarabine Uncertain Watch for early features of toxicity of cytarabine... 

Flucytosin i.v., 0. ind. systemic mycoses, given in combination with amphotericin B resistance when used as monotherapy bone marrow toxicity, nephrotoxicity, hepatotoxicity avoid other nephrotoxic drugs cytarabin as antagonist... 

Central nervous system disturbances, especially impaired cerebellar function, limit doses of cytarabine, and age is an important predictive factor. Of 418 patients who received 36-48 g/m only 35 (8%) had severe cerebellar toxicity, which was irreversible or fatal in 4 (1%) (2). Patients over 50 years of age were significantly more likely to develop cerebellar problems than younger patients (26/137, 19%, compared with 9/281, 3%) a second course did not increase the incidence, implying that it is the individual rather than the cumulative dose that is important. 

The cerebellar syndrome is the most common comph-cation of high-dose cytarabine therapy. In a study of the cerebellar syndrome caused by cytarabine (3), in which it was found in seven of 30 patients treated, symptoms of toxicity appeared between the third and seventh days of chemotherapy, manifesting first as lethargy and confusion (3). Within the next 24 hours there were signs of cerebellar dysfunction, including dysarthria, ataxia, tremor, nystagmus, and dysmetria. In most patients in whom neurotoxicity developed, liver function worsened during chemotherapy. Abnormal liver function at the start of therapy and the development of neurotoxicity appear to be linked. The symptoms of neurotoxicity resolved within 4-49 days. 

Keratoconjunctivitis is a complication of cytarabine therapy, with a reported incidence of 30-100% and commonly associated with high doses (3 g/m ). Corneal and conjunctival toxicity have been described after therapy for 4 days with 235 mg (100 mg/m ) daily (7). 

The addition of cytarabine 10 mg/m /day subcutaneously for 10 days to interferon monotherapy more than doubled the incidence of gastrointestinal toxicity in the treatment of chronic myeloid leukemia in 139 patients (8). 

Thioguanine is u.sed in treating acute leukemia, especially in comhination with cytarabine." - Cro.ss-resistance exists between thioguanine and mercaptopurine. The chief toxic effect is delayed bone marrow depre.ssion. resulting in leukopenia and eventually thrombocytopenia and bleeding. 

The mode of action of mitoxantronc involves intercalation and inhibition of topoisomcrasc 11. In contrast to doxorubicin. it docs not undergo redox cycling to form oxygen free radicals, because iLs redox potential is outside the reductive capability of mammalian reductases. Mitoxantrone is approved for remission-induction therapy in acute nonlympho-cytic leukemia, where it typically is used with cytarabine. It also is active against other leukemias, breast cancer, and ovarian cancer. The dose-limiting toxic effect is myelosup-... 

The toxicity of antimetabolites is, as expected, due to their incorporation into the metabolism of normal cells, which is nearly identical to that of the malignant cells that they were designed to injure. The normal cells injured most severely are the rapidly proliferating cells of the bone marrow, the lymphoid system, and the GI epithelium. Thus, the common toxicities are bone marrow depression, nausea and vomiting, diarrhea, and mucositis. Cytarabine and pentostatin can cause conjunctivitis. Capecitabine and prolonged use of fluorouracil or cytarabine can cause cerebellar ataxia and the hand-foot syndrome, that is, palmar-plantar erythrodysesthesia or acral erythema. Pentostatin and high-dose methotrexate can cause renal toxicity. 

Albumin Albumin is available in highly pure and uniform form and exhibits low toxicity and good biological stability. It has been used as a carrier for methotrexate and a variety of antiviral drugs [amantadine, floxuridine (5-fluorodeoxyuridine), and cytarabine (cytosine arabinoside)] to treat macrophage tumors and infections caused by DNA viruses growing in macrophages. Heavily modified albumins are known to be readily... 

The toxicity of cytarabine is dose dependent. The most characteristic toxicity of high-dose ara-C (HDAC >1 g/m per dose) regimens is a cerebellar syndrome of dysarthria, nystagmus, and ataxia. Risk of CNS toxicity is strongly correlated with advanced age and renal dysfunction. Renal insufficiency permits accumulation... 

Fludarabine monophosphate (FAMP) is an analog of the purine adenine. Like cytarabine, fludarabine interferes with DNA polymerase, causing chain termination. Unlike ara-C, fludarabine is also incorporated into RNA, resulting in inhibited transcription. The usual dose-limiting toxicity is myelosuppression. Fludarabine is also immunosuppressive, with associated opportunistic infections. ... 

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