BCNU toxicity

Our finding of potentiation by SAAB of BCNU cytotoxicity contrasts with other recent reports. Berger et al. [7] failed to detect any S-aminobenzamide (SAB)-medi-ated potentiation of BCNU toxicity to LI 210 mouse leukemic cells, and likewise Boorstein and Pardee [8] detected no enhancement by the same inhibitor of BCNU toxicity to human fibroblasts. This may reflect differences in the cell systems. Alternatively, since SAAB is some 6-8 times more effective as a poly(ADP-ribose) synthetase inhibitor than is SAB [9], it could be that the concentrations of SAB used by Berger et al. [7] and Boorstein and Pardee [8], 10 mM and 4 mM respectively, were not sufficiently high. 

BCNU has been used alone and in combination in the treatment of a variety of malignancies. All documented toxicities include nausea, vomiting and myelosuppression (16, 34, 65, 84, 91, 93). The nadir of leukopenia is approximately 6 weeks and while recovery usually follows rapidly, a case of prolonged cytopenia has been reported. The patient was still granulocytopenic at 20 months. The nadir of thrombocytopenia appears slightly earlier than that of leukopenia, at approximately 4 weeks with full recovery by 6 weeks (65). Attempts to reduce myelosuppression by the concomitant administration of an androgenic steroid (fluoxymesterone) showed no obvious benefit (65). However, this study documented BCNU toxicity in detail and included nausea, vomiting, stomatitis, phlebitis at the injection site, leukopenia and thrombocytopenia. 

Brem, H., Tamargo, R. J., Finn, M., and Chasin, M., Biocompatibility of a BCNU-loaded biodegradable polymer A toxicity study in primates, Abstracts of the 1988 Annual Meeting of the American Association of Neurological Surgeons, 1988,... 

Two TV-nitrosoureas, Bischloroethyl-nitrosourea (BCNU) and l-chloroethyl-3-cyclohexyl-1-nitrosourea (CCNU), have been used as anticancer agents in clinics but their mechanism and their toxicities have yet to be determined78. 

In an effort to overcome the lack of solubility, poor penetration across the blood-brain barrier and decreased delivery of conventional systemic agents by a compromised intratumoral blood supply, several studies have evaluated various combinations of BCNU alone or with other agents delivered intraarterally. Unfortunately, response rates and median survival times observed in patients treated with intraarterial chemotherapy have not been significantly different than those seen in patients treated with standard intravenous nitrosurea-containing regimens, while increased rates of toxicity such as leukoen-cephalopathy, retinal injury, edema, myelosuppression, sepsis, and thrombotic complications have been noted (40-46). 

Carmustine BCNU, BiCNU Primary brain tumors Hodgkin disease non-Hodgkin lymphomas multiple myeloma Blood disorders (thrombocytopenia, leukopenia] Gl distress (nausea, vomiting] hepatotoxicity pulmonary toxicity... 

Retinal toxicity usually begins within 2 to 14 weeks after intra-arterial infusion of BCNU. Approximately 65% of patients develop retinal complications (Box 35-5). It is common to have loss of vision from the retinopathy, and visual acuity can be reduced to 20/60, to light perception, or even to no light perception. A definite relationship... 

In dogs, high doses of BCNU resulted in severe bone marrow hypoplasia with delayed, reversible thrombocytopenia. The other major toxicides observed were cardiopulmonary (pulmonary edema, myocardial infarction, and pericardial hemorrhage), intestinal mucosal damage with hemorrhage, renal toxicity, and delayed hepatotoxicity. Similar toxicity was seen in monkeys except that cardiopulmonary toxicity did not occur. In rats, initially well-tolerated doses may cause death later. There is sufficient evidence for the carcinogenicity of BCNU in rats. BCNU is embryo-and fetolethal in rats and rabbits at doses nontoxic to the mother and can induce a variety of teratogenic effects in rats. 

Clinical signs associated with BCNU-induced pulmonary toxicity in humans are dyspnea, tachypnea, and a dry hacking cough. The incidence of these symptoms is between 20% and 30% and mortality varies from 24% to 80%. The onset of symptoms is usually within 3 years of treatment. There is a linear relationship between total dose received and pulmonary toxicity at doses >I000mgm , with 50% of patients developing pulmonary toxicity at total cumulative doses of 1500 mg m . ... 

BCNU is associated with the highest incidence of pulmonary toxicity (20% to 30%). The lung pathology generally resembles that... 

CNS toxicity is manifest in the form of nausea and vomiting, particularly after intravenous administration of nitrogen mustard or BCNU. Ifosfamide is the most neurotoxic of this class of agents, producing altered mental status, coma, generalized seizures, and cerebellar ataxia. These side effects have been linked to the release of chloroacetal-dehyde from the phosphate-linked chloroethyl side chain of ifosfamide. High-dose busulfan may cause seizures in addition, it accelerates the clearance of phenytoin, an antiseizure medication. 

Having confirmed pCPPrSA pol3rmers are (i) biocompatible and non-toxic with BCNU-loading and possible radiation therapy, (ii) capable of broad BCNU distribution from the implantation site, and (iii) more effective delivery systems than systemic BCNU in animal survival studies, research development progressed to a multicenter phase I-II chnical... 

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