Cancer chemotherapy drugs, such as cisplatin, are extremely potent for producing nausea and vomiting. The acute effects of these treatments are partly controlled using anti-emetic drugs, but the delayed effects (>24 h), especially nausea, are much more difficult to treat. Furthermore, cisplatin induces a long-term (up to 48 h) increase in pica in rats. Pica is manifested as an increase in consumption of kaolin (clay) and is used as a measure of visceral sickness. It is unknown what brain pathways might be responsible for this sickness associated behavior. As a first attempt to define this neural system, rats were injected (i.p.) with 3, 6, or 10 mg/kg cisplatin (doses reported to produce pica) and sacrificed at 6, 24, or 48 h to determine brain Fos expression. The primary results indicate: 1) increasing the dose of cisplatin increased the magnitude and duration of brain Fos expression, 2) most excitatory effects on hindbrain nucleus of the solitary tract (NTS) and area postrema (AP) Fos expression occurred within 24 h after cisplatin injection, 3) 6 and 10 mg/kg cisplatin treatment produced large increases in Fos expression in the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST), including 48 h after injection, and 4) cisplatin treatment produced little effect on Fos expression in the paraventricular and supraoptic nuclei of the hypothalamus. These results indicate that cisplatin activates a neural system that includes the dorsal vagal complex (NTS and AP), CeA, and BNST.

Recent advances in the knowledge of the cellular effects of arsenic have provided insights into the molecular mechanisms of arsenic-associated carcinogenesis, immunotoxicity and cardiovascular disease. In the present experiments we tested the hypothesis that the arrival of arsenic to the gastrointestinal (GI) tract is detected by the gut-brain axis, which includes hindbrain and forebrain nuclei activated by GI stimulation. As a marker of neuronal activation we measured Fos expression using immunohistochemistry. Because Fos expression in these nuclei is closely linked to the development of conditioned flavor aversion (CFA) we also tested the effect of arsenic on CFA. Our experiments indicate that arsenic ingestion is readily detected by the brain, as shown by increased Fos expression after oral administration of arsenic. Furthermore, the vagus nerve, which supplies information from the GI tract to the brain, is not involved in this response because a complete subdiaphragmatic vagotomy did not reduce the effect of arsenic on brain Fos expression, but enhanced this response. In parallel, arsenic ingestion is associated with a robust, dose-dependent CFA, which started at doses as low as 0.1 mg/kg body weight. In summary, these data indicate that arsenic given by oral administration is detected by the brain in low concentrations, and activates specific nuclei, which might trigger behavioral responses, such as CFA.

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Ofatumumab (OFA) is a fully human CD20 monoclonal antibody (mAb) recently approved for treatment of patients with fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia (CLL). OFA binds a unique membrane-proximal epitope encompassing both the small- and large-loop on the CD20 receptor. Its mechanism of action includes complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Combining OFA with cytotoxic chemotherapy may lead to elimination of additional tumor cells by alternate mechanisms such as apoptosis via alkylating agents. We conducted preclinical studies to determine: 1) OFA activity in B-cell lymphoma and leukemia murine xenograft models with differential CD20 expression; and 2) activity of combining OFA with bendamustine in a CLL model. CD20 expression on tumor cell lines was determined by flow cytometry, and lymphoma (Ramos, Daudi) and CLL (JVM-3) lines with differential CD20 expression were selected for in vivo animal model development. CD20-negative BC-1 lymphoma model served as a control. Tumor cells were implanted s.c. into immunodeficient 4-6 weeks old C.B-17 SCID female mice (Taconic), and tumor volumes were determined twice a week based on caliper measurements (tumor volume = width2 × length/2). Mice were randomized and therapy was initiated when tumors reached mean volume (V) = 80 mm3 at two weeks after tumor implantation. OFA was administered i.p. twice a week, and bendamustine was injected in a single i.v. dose on day 15 of the study. Efficacy of therapy was determined by evaluating % tumor growth inhibition (TGI=100x(1-(Vt/Vc), where Vt, Vc = mean V in the treated, or control group, respectively) and tumor growth delay (TGD=100x((Tt-Tc)/Tc) where Tt, Tv = time to end-point in the treated, or control group). CD20 expression ranged from highest to lowest on Ramos, JVM-3 and BC-1 (CD20 negative) cells. All cell lines were tumorigenic in C.B-17 SCID mice. OFA monotherapy was effective in the Ramos and JVM-3, but not in the control BC-1 s.c. xenograft model. OFA dose-response was performed and suboptimal doses of OFA (2 mg/kg i.p.) and bendamustine (50 mg/kg i.v.) were used for chemotherapy combination studies in the JVM-3 s.c. xenograft model. Combination therapy resulted in a synergistic anti-tumor activity with TGI = 96% and TGD = 42%, compared to bendamustin (TGI = 9%, TGD = 14%) or OFA alone (TGI = 16%, TGD = 14%) in the CLL model. In conclusion, single-agent therapy with OFA demonstrated significant and dose-dependent activity in preclinical animal xenograft models of human B-cell lymphoma and CLL. The combination of suboptimal OFA and bendamustine doses in the CLL model resulted in significant antitumor activity, compared exposure to either agent alone. These preclinical findings provide a rationale for clinical studies of the combination of OFA and bendamustine in patients with CLL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-317.