Phase I study of high-dose cytosine arabinoside and etoposide in patients with advanced malignancies

Summary Cytosine arabinsodie (ara-C) and etoposide (VP-16) display synergy in the laboratory. Twenty-six patients participated in a phase I study of high-dose ara-C in combination with VP-16. The dose of VP-16 was held constant at 50 mg/m² as an intermittent infusion over 33 h; escalating doses of ara-C were given as infusions during hours 9–12 and 21–24. Myelosuppression was the dose-limiting toxicity and occurred with doses considerably less than those expected from studies of the two drugs as single agents. The suggested initial doses for phase II trials with this schedule are 750 mg/m²×2 doses of ara-C and 50 mg/m² of VP-16. Nonhematologic toxicity was minimal; therefore, further dose escalation is feasible in patients in whom myelosuppression is acceptable.Supported in part by grants from the National Cancer Institute (CA-12197 and CA-09422) and the American Cancer Society CF-85-182     

Administration of kainic acid and colchicine alters mu and lambda opiate binding in rat hippocampus

Quantitative in vitro autoradiography was used to assess the effects of kainic acid (KA) and colchicine (COL) on mu and lambda opiate binding in the rat hippocampus. Rats were treated with either systemic KA, a neurotoxin that damages CA3 pyramidal cells and causes seizures and wet-dog shakes, or intrahippocampal COL to destroy dentate granule cells and their mossy fibers, or both toxins. Moderate levels of mu binding were detected in the pyramidal layer and in the stratum lacunosum-moleculare; binding was greater in the ventral hippocampus. Levels of mu binding were markedly increased in all regions 48 h after treatment with KA. Two weeks after COL treatment, there was a modest decrease in mu binding; COL plus KA gave results similar to COL alone. Dense lambda binding was present over the mossy fibers in the stratum lucidum, but was absent over the pyramidal layer. In contrast to mu binding, lambda binding was greater in the dorsal hippocampus. KA alone had little effect on lambda binding, whereas COL alone caused large decreases. KA plus COL caused even larger decreases in lambda binding, to as much as 85% below control. These results demonstrate that mu and lambda binding are localized to different parts of the hippocampus, respond differently to neurotoxin lesions, and likely serve different roles in this brain region. The number of mu sites is responsive to the release of enkephalin; these receptors appear to be linked to opiate-induced hippocampal seizure activity, especially wet-dog shakes. Lambda sites may serve as autoreceptors on mossy fibers.     

Toxicity, inflammation, and anti-human immunodeficiency virus type 1 activity following exposure to chemical moieties of C31G.

C31G, which has potent activity against the human immunodeficiency virus type 1 (HIV-1) and an established record of safety in animal studies and human trials, is a microbicidal agent comprised of a buffered equimolar mixture of two amphoteric, surface-active agents: an alkyl amine oxide (C14AO) and an alkyl betaine (C16B). Studies of long-term in vitro exposure to C31G and its constituents have suggested that the components of C31G may contribute differentially to its toxicity and efficacy. In the present studies, in vitro assays of cytotoxicity and anti-HIV-1 activity demonstrated that C16B was slightly less cytotoxic compared to either C31G or C14AO, whereas the anti-HIV-1 activities of C31G and its individual constituents were similar. In the murine model of cervicovaginal microbicide toxicity, in vivo exposure to C14AO resulted in severe cervical inflammation followed by a delayed disruption of the columnar epithelium. In contrast, exposure to C16B caused severe cervical epithelial disruption and a secondary, less intense inflammatory response. These results demonstrate that (i) there are both mechanistic and temporal differences in toxicity associated with the components of C31G not necessarily predicted by in vitro assessments of cytotoxicity and (ii) contributions of each component to the anti-HIV-1 activity of C31G appear to be equal. In addition, these findings indicate that direct and indirect mechanisms of in vivo toxicity can be observed as separate but interrelated events. These results provide further insight into the activity of C31G, as well as mechanisms potentially associated with microbicide toxicity.     

Castleman disease: surgical cure in pediatric patients

Castleman disease is a rare disorder characterized by lymphoid hyperplasia which rarely manifests in children. We present 2 cases which highlight both histologic variants of this disease, and provide suggestions regarding workup and treatment with the goal of making practitioners aware of Castleman disease in the differential diagnosis of a child presenting with vague symptoms.