thioinosine and Body-Weight

Our objectives were to study the biological activity of a novel gemcitabine-cardiolipin conjugate (NEO6002) and compare that with gemcitabine. Cytotoxicity in vitro was determined against several gemcitabine-sensitive parental and gemcitabine-resistant cancer cell lines using the sulforhodamine B assay. The in vivo toxicity was examined by changes in body weight and hematologic indices of conventional mice. Immunodeficient SCID mice bearing P388 and BxPC-3 tumor xenografts were used to evaluate the in-vivo therapeutic efficacy. Both NEO6002 and gemcitabine showed pro-apoptotic and cytotoxic effects against all gemcitabine-sensitive cell lines tested. Unlike gemcitabine, the cytotoxicity of NEO6002 was independent of nucleoside transporter (NT) inhibitors, indicating a different internalization route of NEO6002. The conjugate demonstrated a favorable activity not only in ARAC-8C, a NT-deficient gemcitabine-resistant human leukemia cell line, but also in several other gemcitabine-resistant cell lines. At the in-vivo level, a comparative toxicity study showed a significant body weight loss and a decrease in white blood cell counts in gemcitabine-treated mice, whereas the influence of NEO6002 was mild. Treatment of NEO6002 at 27 micromol/kg increased the median survival of CD2F1 mice bearing P388 cells by up to 73%, while at the same doses and schedule of gemcitabine resulted in toxic deaths of all treated mice. At a dose of 18 micromol/kg, NEO6002 inhibited the growth of BxPC-3 xenografts by 52%, while only 32% of tumor inhibition was achieved with gemcitabine. We conclude that NEO6002 may be an effective chemotherapeutic agent with improved tolerability and can potentially circumvent NT-deficient, gemcitabine-resistant tumors.

Topics: Animals; Antineoplastic Agents; Body Weight; Cardiolipins; Cell Proliferation; Deoxycytidine; Dipyridamole; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Gemcitabine; HT29 Cells; Humans; Leukemia P388; Leukocyte Count; Mice; Mice, SCID; Neutropenia; Nucleoside Transport Proteins; Pancreatic Neoplasms; Thioinosine; Xenograft Model Antitumor Assays

We investigated the effects of dietary MaxEPA (a major source of eicosapentaenoic acid in fish oil) supplementation on blood pressure (BP) responses and heart rate (HR) of Dahl salt-sensitive (SS) rats fed low (0.4% NaCl) and high (8.0% NaCl) sodium diets. During a four week treatment period, BP remained normotensive in rats on low salt diet but was significantly elevated in those on high salt diet, causing 50% mortality. MaxEPA diminished the BP elevation and prevented the high salt-induced mortality. HR was not affected by either salt diet alone but was reduced in the presence of MaxEPA. At the end of the treatment period, the distribution of [3H]nitrobenzylthioinosine ([3H]NBMPR) binding, a putative marker of adenosine transport and metabolism, was estimated in selected rat tissues in order to evaluate the role of the purinergic system in the BP lowering effect of MaxEPA. Maximal [3H]NBMPR binding capacity (Bmax) in the kidney and platelets were 39% and 82% lower, respectively, in rats on high salt diet than in those on low salt diet. MaxEPA significantly blunted the decrease in Bmax in the kidney but not in platelets and increased Bmax in heart (48%) of low salt group. There were no changes in dissociation constants (Kd). The results suggest that MaxEPA can attenuate salt-induced hypertension, reduce salt-induced mortality and protect the integrity of kidney NBMPR binding sites in salt-induced hypertension.

Topics: Affinity Labels; Animals; Binding Sites; Blood Platelets; Blood Pressure; Body Weight; Dietary Fats, Unsaturated; Docosahexaenoic Acids; Drug Combinations; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Heart Rate; Hypertension; Kidney; Male; Rats; Rats, Sprague-Dawley; Sodium Chloride, Dietary; Thioinosine