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While first-generation taxanes are valuable treatment options for many solid tumors, they are limited by an inability to cross the blood-brain barrier (BBB) and by limited efficacy in pediatric patients. Following promising preclinical data for the next-generation taxane cabazitaxel, including activity in tumor models fully sensitive, poorly sensitive or insensitive to docetaxel, and its ability to cross the BBB, further preclinical studies of cabazitaxel relevant to these two clinical indications were performed.Cabazitaxel brain distribution was assessed in mice, rats and dogs. Cabazitaxel antitumor activity was assessed in mice bearing intracranial human glioblastoma (SF295; U251) xenografts, and subcutaneous cell line-derived human pediatric sarcoma (rhabdomyosarcoma RH-30; Ewing's sarcoma TC-71 and SK-ES-1) or patient-derived pediatric sarcoma (osteosarcoma DM77 and DM113; Ewing's sarcoma DM101) xenografts. The activity of cabazitaxel-cisplatin combination was evaluated in BALB/C mice bearing the syngeneic murine colon adenocarcinoma, C51.Cabazitaxel penetrated rapidly in the brain, with a similar brain-blood radioactivity exposure relationship across different animal species. In intracranial human glioblastoma models, cabazitaxel demonstrated superior activity to docetaxel both at early (before BBB disruption) and at advanced stages, consistent with enhanced brain penetration. Compared with similar dose levels of docetaxel, cabazitaxel induced significantly greater tumor growth inhibition across six pediatric tumor models and more tumor regressions in five of the six models. Therapeutic synergism was observed between cisplatin and cabazitaxel, regardless of administration sequence.These preclinical data suggest that cabazitaxel could be an effective therapy in CNS and pediatric tumors, supporting ongoing clinical evaluation in these indications.

Mouse colon adenocarcinoma Co38 is widely used as a screening model for human colon tumors. To understand better the influence of tumor size on the main drug-metabolizing enzyme systems, we tested 15 mouse Co38 tumors at different sizes. The average weight was 917 +/- 444 mg (range, 300-1,400 mg). Cytochromes P-450 (1A1/1A2, 2B1/B2, 2C8-10, 2E1, 3A4), epoxide hydrolase (EH), and glutathione-S-transferases (GST-alpha, -mu, and -pi) were assayed by immunoblotting. The activities of the following enzymes or cofactors were determined by spectrophotometric or fluorometric assays: 1-chloro-2,4-dinitrobenzene-GST (CDNB-GST), selenium-independent glutathione peroxidase (GPX), 3,4-dichloronitrobenzene-GST (DCNB-GST), ethacrynic acid-GST (EA-GST), total glutathione (GSH), uridine diphosphate-glucuronosyltransferase (UDP-GT), beta-glucuronidase (beta G), sulfotransferase (ST), and sulfatase (S). Our results showed the absence of all probed P-450s and EH in Co38 tumors. No relationship was found between the Co38 tumor weights and GPX, GST-alpha, and EA-GST (regression analysis). However, a significant correlation was found between the tumor weights and all other enzymes investigated. For certain enzymes or cofactors, a linear decrease (P0.05) was observed as a function of tumor weight (CDNB-GST, DCNB-GST, GST-mu, GST-pi, GSH, and beta G). Other enzymatic activities (UDP-GT, S, and ST) were found to decrease in medium-size tumors and to increase in large tumors (P0.05; quadratic correlation). These data demonstrate that the expression of many drug-metabolizing enzyme systems is altered during tumor growth and suggest that tumoral response to chemotherapy could be altered as a function of tumor size.

Flavone acetic acid (FAA; LM 975; NSC 347512) is a new anticancer agent with unprecedented, broad antitumor activity in murine models. Although FAA is very effective in vivo against solid tumors, including colon 38 adenocarcinoma, it was not cytotoxic in vitro against colon 38 cells and human colon adenocarcinoma cells HCT116 at pharmacologically achievable concentrations and exposure times. For example, a concentration of 300 micrograms/ml for a 10-day exposure time was required to obtain less than 1 log cell kill. After the administration of an effective FAA dose (180 mg/kg, i.v.) to mice, plasma cytotoxicity against HCT116 cells attained a 2 log cell kill between 0.5 and 2 h, which decreased to 1 log cell kill at 4 h. No cytotoxicity was observed 6, 12 or 21 h after drug administration. The controls used comprised mouse plasma containing FAA concentrations similar to those assayed in the above plasma samples from in-vivo-dosed mice. These spiked plasma were not cytotoxic, indicating that other cytotoxic species, formed in vivo, were responsible for the increased cytotoxicity. Mouse hepatocytes co-cultured with HCT116 cells increased FAA cytotoxicity to 1 log cell kill at 30-100 micrograms/ml. The addition of phenobarbital-induced mouse liver supernatant S-9000xg also markedly increased FAA cytotoxicity to a 2 log cell kill at 300 micrograms/ml. We conclude that FAA can be activated both in vivo and in vitro to cytotoxic species that are more active than the parent compound.

Flavone acetic acid (FAA) is a novel antitumor agent with broad solid-tumor activity. However, this drug has shown a steep dose-response curve in preclinical trials, with a narrow sublethal window of efficacy. To investigate this threshold behavior, we studied various aspects of FAA pharmacology in mice after i.v. administration. Mice bearing advanced-stage s.c. colon 38 adenocarcinoma were treated at four dose levels (39, 65, 108, and 180 mg/kg), and only the highest dose produced significant antitumor activity, showing a steep dose-response curve. Using an HPLC assay, FAA pharmacokinetics in both plasma and tumors were found to be dose-dependent. As the dose increased, there was a decrease in both total body clearance and volume of distribution at steady state. The increase in tumor area under the curve (AUC) was more pronounced than the corresponding increase in plasma AUC, showing a better tumor exposure to FAA at high doses. The distribution of FAA in normal tissues showed a short-term retention in the liver and kidneys; low concentrations were observed in the heart, spleen, and brain, with some retention in the latter. The highest FAA concentrations were found in the gastrointestinal (GI) tract, mainly in the duodenum, suggesting an important biliary excretion of the drug. Various possible causes of FAA nonlinear pharmacokinetics were investigated. Serum protein binding was high (79%) and remained constant up to 100 μg/ml, but decreased thereafter at higher FAA concentrations, e.g., 76% at 500 μg/ml and 64% at 1,000 μg/ml. Urinary and biliary clearances were dose-dependent and decreased 5- and 9-fold, from the 39- to the 180-mg/kg dose levels, respectively. A direct assessment of FAA enterohepatic circulation using intercannulated mice showed that 27% of the plasma AUC was accounted for by enterohepatic circulation. FAA acyl glucuronide was identified as the major metabolite in mice and was found to contribute to the nonlinear pharmacokinetics due to its facile hydrolysis under physiological conditions, regenerating FAA. In conclusion, the steep FAA dose-response curve was found to be caused by dose-dependent pharmacokinetics in mice. The nonlinear pharmacokinetics of this drug was attributed to a dose-dependent decrease in both urinary and biliary clearances, concentration-dependent serum protein binding, enterohepatic circulation, and the instability of FAA acyl glucuronide under physiological conditions, forming a futile cycle. The distribution data also suggested possible tissue targets for anticancer efficacy and/or toxicity that could be useful in designing clinical studies.