Predictors of depression in multiple sclerosis patients.

Depression is one of the major problems associated with multiple sclerosis (MS). Several physical and psychological factors tend to interact and make it difficult to pinpoint the predictors of the depression. It seemed particularly important to examine how anxiety and illness evolution (characterized by the functional status) influence the appearance of depression symptoms. Thus, the aim of this article was to clarify the relationship between depression and the factors associated with it. One hundred and fifteen participants living at home recruited through various associations and MS clinics answered socio demographic, medical and psychological questions and questionnaires (depression, anxiety, coping, social support, locus of control, alexithymia, self-esteem). Results show that functional status (EDSS), trait anxiety, alexithymia and satisfaction with social support system are the predicting factors of depression. Trait anxiety and functional status are two predictors that independently and simultaneously lead to the appearance of depression symptoms, with trait anxiety playing a predominant role. Alexithymia and social support indirectly influence the appearance of these symptoms.

Differences in effective connectivity between dyslexic children and normal readers during a pseudoword reading task: an fMRI study.

PURPOSE: This fMRI study investigated phonological and lexicosemantic processing in dyslexic and in chronological age- and reading level-matched children in a pseudoword reading task. MATERIALS AND METHODS: The effective connectivity network was compared between the three groups using a structural model including the supramarginal cortex (BA 40; BA: Brodmann area), fusiform cortex (BA 37) and inferior frontal cortex (BA 44/45) areas of the left hemisphere. RESULTS: The results revealed differences in connectivity patterns. In dyslexic patients, in contrast with chronological age- and reading level-matched groups, no causal relationship was demonstrated between BA 40 and BA 44/45. However, a significant causal relationship was demonstrated between BA 37 and BA 44/45 both in dyslexic children and in the reading level-matched group. CONCLUSIONS: These findings were interpreted as evidence for a phonological deficit in developmental dyslexia.

Fluorescence anisotropy of cell membranes of doxorubicin-sensitive and -resistant rodent tumoral cells.

We have studied the plasma membrane fluidity of rat C6 glioblastoma cells and simian virus 40-transformed mouse liver cells in culture that had been rendered resistant to doxorubicin. This was done by the evaluation of fluorescence anisotropy of two probes; diphenylhexatriene was used on membrane microsomal fractions, and trimethylammonium-diphenylhexatriene was used on whole cell suspensions as a plasma membrane-specific probe since it does not enter the cells. A higher degree of membrane fluidity was exhibited with both techniques by doxorubicin-resistant glioblastoma cells as compared to the doxorubicin-sensitive strain, but in the transformed liver cells no such alteration was seen in the physical properties of their plasma membranes. A higher degree of acyl group unsaturation was noticed in the glioblastoma cells but not in the transformed liver cells upon acquisition of doxorubicin resistance. A similar simultaneous increase in acyl group unsaturation and membrane fluidity can be obtained easily by growing the sensitive cells with a medium supplemented with exogenous polyunsaturated fatty acids. This alteration does not modify the sensitivity of the cells to doxorubicin. We conclude from our work that the increase in membrane fluidity, which is frequently associated with drug resistance, is neither necessary nor sufficient for the expression of the resistance. The reason for a link between cell resistance to doxorubicin and plasma membrane fluidity remains to be found.

Fatty acid composition transport and metabolism in doxorubicin-sensitive and-resistant rat glioblastoma cells.

We have studied the lipid composition and the acyl group composition, transport, and metabolism of doxorubicin-sensitive and -resistant rat glioblastoma cells in monolayer cultures (C6 clone). No difference in lipid composition was evidenced; the acyl group composition was, in contrast, highly modified in resistant cells, and these modifications appeared progressively during the acquisition of the resistance. Resistant cells were characterized by a decrease of n-9 eicosatrienoic acid and by a 2-3-fold increase of the proportions of the polyunsaturated fatty acids of the n-6 and n-3 families, especially arachidonic acid and n-3 docosahexaenoic acid. These differences were probably due to a 2-fold increase of the uptake of fatty acids by resistant cells as compared to sensitive cells, this increase allowing the suppression of an essential fatty acid deficiency. Only small changes in the transformations of 16 and 18-carbon atoms' fatty acids to higher analogues were evidenced. A small reduction of the desaturation of stearic acid to oleic acid and of linoleic acid to arachidonic acid was the main characteristic of resistant cells; these differences can be explained as a consequence of the suppression of the essential fatty acid deficiency.

Docetaxel chronopharmacology in mice.

Docetaxel tolerance and antitumor efficacy could be enhanced if drug administration was adapted to circadian rhythms. This hypothesis was investigated in seven experiments involving a total of 626 male B6D2F1 mice, synchronized with an alternation of 12 h of light and 12 h of darkness (12:12), after i.v. administration of docetaxel. In experiment (Exp) 1, the drug was given once a week (wk) for 6 wks (20 mg/kg/wk) or for 5 wks (30 mg/kg/wk) at one of six circadian times, during light when mice were resting [3, 7, or 11 hours after light onset (HALO)], or during darkness, when mice were active (15, 19, or 23 HALO). Endpoints were survival and body weight change. In Exp 2 and 3, docetaxel (30 mg/kg/wk) was administered twice, 1 wk apart, at one of four circadian stages (7, 11, 19, or 23 HALO). Endpoints were hematological and intestinal toxicities. In Exp 4, circadian changes in cell cycle phase distribution and BCL-2 immunofluorescence were investigated in bone marrow as possible mechanisms of docetaxel tolerability rhythm. In Exp 5 to 7, docetaxel was administered to mice bearing measurable P03 pancreatic adenocarcinoma (270-370 mg), with tumor weight and survival as endpoints. Mice from Exp 5 and 6 received a weekly schedule of docetaxel at one of six circadian stages (20 or 30 mg/kg/wk at 3, 7, 11, 15, 19, or 23 HALO). In Exp 7, docetaxel (30 mg/kg) was given every 2 days (day 1, 3, 5 schedule) at 7, 11, 19, or 23 HALO. Docetaxel dosing in the second half of darkness (19 or 23 HALO) resulted in significantly worse toxicity than its administration during the light span (3, 7, or 11 HALO). The survival rate ranged from 56.3% in the mice treated at 23 HALO to 93.8 or 87.5% in those injected at 3 or 11 HALO, respectively (Exp 1, P < 0.01). Granulocytopenia at nadir was -49 +/- 14% at 7 HALO compared with -84 +/- 3% at 19 HALO (Exp 2 and 3, P < 0.029), and severe jejunal mucosa necrosis occurred in 5 of 8 mice treated at 23 HALO as opposed to 2 of 18 receiving docetaxel at 7, 11, or 19 HALO (Exp 2 and 3, P < 0.02). The time of least docetaxel toxicity corresponded to the circadian nadir in S or G2-M phase and to the circadian maximum in BCL-2 immunofluorescence in bone marrow. Docetaxel increased the median survival of tumor-bearing mice in a dose-dependent manner (controls: 24 days; 20 mg/kg weekly, 33 days; 30 mg/kg weekly or day 1, 3, 5 schedule, 44 or 46 days, respectively; Exp 5-7). Survival curves of treated mice differed significantly according to dosing time for each dose and schedule (P from log rank <0.003 to P < 0.03). In Exp 5 and 6, the percentage of increase in life span was largest if docetaxel was administered weekly at 7 HALO (20 mg/kg, 220%; 30 mg/kg, 372%) and lowest after docetaxel dosing at 19 HALO (80% with 20 mg/kg) or at 15 HALO (78% with 30 mg/kg). In Exp 7, (day 1, 3, 5 schedule), docetaxel was most active at 11 HALO (percentage increase in life span, 390%) and least active at 23 HALO (210%). Docetaxel tolerability and antitumor efficacy were simultaneously enhanced by drug dosing in the light span, when mice were resting. Mechanisms underlying the tolerability rhythm likely involved the circadian organization of cell cycle regulation. Docetaxel therapeutic index may be improved with an administration at night in cancer patients, when fewest bone marrow cells are in S or G2-M phase.

Experimental chronotherapy of mouse mammary adenocarcinoma MA13/C with docetaxel and doxorubicin as single agents and in combination.

The therapeutic index of docetaxel, doxorubicin and their combination may be improved by an adequate selection of the circadian time of administration. The present study constitutes a prerequisite to testing the clinical relevance of chronotherapy in human breast cancer. Three experiments were performed in C3H/HeN mice. Each treatment modality was administered i.v. once a week for 3 weeks at one of six circadian stages, during the light span, when the mice were resting: 3, 7, and 11 h after light onset (HALO), or during darkness, when the mice were active: 15, 19, and 23 HALO. The circadian time dependency of single agent tolerability was investigated in healthy mice using four dose levels for docetaxel (38.8, 23.3, 14, and 8.4 mg/kg/injection) and for doxorubicin (13.8, 8.3, 5 and 3 mg/kg/injection; experiment 1). The circadian time dependency of each single agent efficacy was studied in MA13/C-bearing mice, using two dose levels of docetaxel (38.8 or 23.3 mg/kg/injection) or doxorubicin (8.3 or 5 mg/kg/injection; experiment 2). The toxicity and the efficacy of the simultaneous docetaxel-doxorubicin combination were assessed as a function of dosing time in experiment 3. Two combinations were tested (A, 16.3 mg/kg/injection of docetaxel and 2.5 mg/kg/injection of doxorubicin; and B, 11.6 and 3.5 mg/kg/injection, respectively) at each of the above six circadian times. Mortality, body weight change, and tumor size were recorded for 60-70 days in each experiment. Single agent docetaxel or doxorubicin was significantly best tolerated near the middle of the rest span (7 HALO) and most toxic in the middle of the activity phase (19 HALO). Docetaxel or doxorubicin as a single drug were also most effective at 7 HALO, irrespective of dose. Treatment at 7 HALO produced highest rates of complete tumor inhibition (81% versus 11% at 3 HALO for docetaxel, p from chi2 <0.001, and 69% versus 44% at 11 HALO for doxorubicin, not significant) and highest day 60 survival rate (100% versus 28% at 3 HALO for docetaxel, p from chi2 <0.001 and 89% versus 69% at 15 HALO for doxorubicin, not significant). Docetaxel-doxorubicin combinations were most effective following dosing in the beginning of the rest span or short after the onset of the activity span, with regard to the rates of both complete tumor inhibitions (45% at 3 HALO versus 15% at 19 HALO) and day 70 survival rates (85% and 80% at 3 and 7 HALO respectively, versus 20% at 19 HALO). The efficacy of single agent docetaxel or doxorubicin and that of their combination varied largely as a function of circadian dosing time. Single agent docetaxel at 7 HALO was the best treatment option in this model with regard to both tolerability and efficacy. This timing may correspond to the middle of the night in cancer patients.

Free fatty acid uptake is increased in doxorubicin-resistant rat glioblastoma cells.

We have investigated the mechanism by which the rat glioblastoma C6 cell line resistant to doxorubicin presented an increase of free fatty acid utilization from the nutrient source as compared to the wild sensitive strain. We have shown that this was not due to an accelerated turnover of the phospholipid hydrophobic or hydrophilic moieties, but to an important increase of the uptake of the free fatty acids. This was demonstrated by studies performed with linoleic and linolenic acids during very short incubations, at low temperatures, and in the absence of albumin in the medium. This enhancement of free fatty acid uptake may explain the differences which exist in the acyl group composition of membrane lipids between doxorubicin-sensitive and -resistant C6 cells, because of the suppression of the essential fatty acid-deficient status of the cells.

Alteration of ganglioside composition and metabolism in doxorubicin-resistant rat tumoral cells.

We have investigated the ganglioside levels, composition and metabolism in two lines of doxorubicin-resistant cells and in the corresponding wild strains, the C6 rat glioblastoma and the HTC rat hepatoma. The only ganglioside present was GM3, and its level was increased 2-fold in C6 resistant cells and decreased nearly 2-fold in HTC resistant cells. A decrease of cytidine 5'-monophospho-N-acetylneuraminic acid:galactosylglucosylceramide sialyltransferase activity was observed in both resistant lines as compared to sensitive ones, and could not, therefore, explain the increase in the GM3 level observed in the C6 resistant line. Alterations of acid neuraminidase activity were also observed; a 5-fold decrease was noticed in the C6 resistant line and could account for the increase in the GM3 level observed in these cells; in contrast, a 2-fold increase of acid neuraminidase activity was noticed in the HTC resistant cells: together, with reduced synthesis, it could explain the decrease in the GM3 level observed in these cells. No alterations of exogenous ganglioside transport was exhibited by the C6 resistant cells.

Preclinical profile of docetaxel (taxotere): efficacy as a single agent and in combination.

Docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) is a new taxoid currently being studied in phase II and III clinical trials worldwide, with promising activity in breast cancer. Docetaxel was evaluated as a single agent against against seven mammary tumors, five from mice and two of human origin. Six of the seven models were found to be sensitive to docetaxel, exhibiting regressions of advanced-stage disease in murine models (MA16/C, MA13/C), and long tumor growth delays (Calc18) and cures (MX-1) in human tumor xenografts. In combination studies in tumor-bearing mice, synergism with docetaxel was observed with cyclophosphamide, 5-fluorouracil, etoposide, vinorelbine (Navelbine; Pierre Fabre Oncologie, Boulogne, France), and methotrexate. A similar level of efficacy was obtained in the cases of docetaxel/vincristine and docetaxel/mitomycin C, compared with the activity of the best single agent. Good activity was obtained with the docetaxel/doxorubicin, docetaxel/vinblastine, and docetaxel/cisplatin combinations; however, the activity of these combinations was lower than that of the best agent in the combination when tested in monotherapy. In terms of tolerance, 60% to 70% of the highest nontoxic dose of each agent could be administered in combination, except for vinca alkaloids, in which 80% to 100% of the maximum tolerated dose did not cause additional toxicity. Although docetaxel is a very potent agent when used in monotherapy, the above results suggest that it also will have a key role in clinical combination chemotherapy.

Preclinical evaluation of docetaxel (Taxotere).

Progress in cancer chemotherapy has been made owing to the discovery and development of drugs that have new structures, new mechanisms of action, and high levels of experimental antitumor activity. Docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) is prepared by semisynthesis from 10-deacetyl baccatin III, an inactive taxoid precursor extracted from the needles of the European yew Taxus baccata. Docetaxel has been found to promote tubulin assembly in microtubules and to inhibit their depolymerization. As predicted by its unique biochemical mechanism of action, docetaxel acts as a mitotic spindle poison and induces a mitotic block in proliferating cells. In vitro, the docetaxel concentrations required to reduce murine and human cell survival by 50% range from 4 to 35 ng/mL, and the cytotoxic effects are greater on proliferating cells than on nonproliferating cells. Docetaxel also is cytotoxic at clinically relevant concentrations against fresh human tumor biopsy specimens (breast, lung, ovarian, colorectal cancer, melanoma) in a soft agar cloning system. Docetaxel has significant in vivo antitumor activity in the different models generally used for the preclinical evaluation of drugs. Eleven of 12 murine transplantable tumors in syngeneic mice have been found to be sensitive to intravenous docetaxel with complete regressions of advanced-stage tumors. Activity also has been observed with human tumor xenografts in nude mice at an advanced stage. In combination studies, synergism has been observed in vivo with 5-fluorouracil, cyclophosphamide, etoposide, vinorelbine, and methotrexate. Preclinical toxicity in mice and dogs has been evaluated by using one and five daily intravenous doses, respectively. The dog was found to be the more sensitive species. The dose-limiting toxicities are hematologic and gastrointestinal in both species. Neurotoxicity also has been observed at high dosages in mice.

Synthesis and structure-activity relationships of new antitumor taxoids. Effects of cyclohexyl substitution at the C-3' and/or C-2 of taxotere (docetaxel).

Synthesis and cytotoxicity of the new analogs (11-13) of docetaxel possessing cyclohexyl groups instead of phenyl groups at the C-3' and/or C-2 benzoate positions are described. The C-2 cyclohexanecarboxylate analog of paclitaxel (15) is also synthesized for comparison. The potency of these new taxoids were examined for their inhibitory activity for microtubule disassembly and also for their cytotoxicity against murine P388 leukemia cell line as well as doxorubicin-resistant P388 leukemia cell line (P388/Dox). It is found that 3'-dephenyl-3'-cyclohexyldocetaxel (11) (0.72T) and 2-(hexahydro)docetaxel (12) (0.85T) possess strong inhibitory activity for microtubule disassembly equivalent to docetaxel (0.7T), which is more potent than paclitaxel (1.0T). The results clearly indicate that phenyl or an aromatic group at C-3' or C-2 is not a requisite for strong binding to the microtubules. This finding has opened an avenue for development of new nonaromatic analogs of docetaxel and paclitaxel. 3'-Dephenyl-3'-cyclohexyl-2-(hexahydro)docetaxel (13) (2T) turns out to be a substantially weaker inhibitor. The cytotoxicities of 11-13 against P388 are, however, in the same range that is 8-12 times weaker than docetaxel and 4-6 times weaker than paclitaxel, i.e., 13 shows equivalent cytotoxicity to that of 11 or 12 in spite of much lower microtubule disassembly inhibitory activity. The cytotoxicities of these new taxoids against the P388/Dox cell line are only 2-2.5 times lower than that of docetaxel. The potency of 2-(hexahydro)paclitaxel (15) for these assays is much lower than the docetaxel counterpart 12. The significant loss of activity in vivo against B16 melanoma is observed for 11-13, i.e., 11 is only marginal (T/C = 38% at 20 mg/kg/day), and 12 and 13 are inactive (T/C = 76% and 79%, respectively). This could be ascribed to faster metabolism, faster excretion or other bioavailability problems.

Syntheses and structure-activity relationships of the second-generation antitumor taxoids: exceptional activity against drug-resistant cancer cells.

A series of new 3'-(2-methyl-1-propenyl) and 3'-(2-methylpropyl) taxoids with modifications at C-10 was synthesized by means of the beta-lactam synthon method using 10-modified 7-(triethylsilyl)-10-deacetylbaccatin III derivatives. The new taxoids thus synthesized show excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A549), colon (HT-29), and breast (MCF-7) cancer cell lines. All but one of these new taxoids possess better activity than paclitaxel and docetaxel in the same assay, i.e., the IC50 values of almost all the taxoids are in the subnanomolar level. It is found that a variety of modifications at C-10 is tolerated for the activity against normal cancer cell lines, but the activity against a drug-resistant human breast cancer cell line expressing MDR phenotype (MCF7-R) is highly dependent on the structure of the C-10 modifier. A number of the new taxoids exhibit remarkable activity (IC50 = 2.1-9.1 nM) against MCF7-R. Among these, three new taxoids, SB-T-1213 (4a), SB-T-1214 (4b), and SB-T-1102 (5a), are found to be exceptionally potent, possessing 2 orders of magnitude better activity than paclitaxel and docetaxel. The observed exceptional activity of these taxoids may well be ascribed to an effective inhibition of P-glycoprotein binding by the modified C-10 moieties. The new taxoid SB-T-1213 (4a) shows an excellent activity (T/C = 0% at 12.4 and 7.7 mg/kg/dose, log10 cell kill = 2.3 and 2.0, respectively) against B16 melanoma in B6D2F1 mice via intravenous administration.

Early-phase pharmacokinetics of doxorubicin in non-Hodgkin lymphoma patients. Dose-dependent and time-dependent pharmacokinetic parameters.

The early-phase (20 min) pharmacokinetics of doxorubicin was studied in 18 patients suffering from non-Hodgkin lymphoma and receiving various schedules and/or dosages of the drug. This pharmacokinetics was time-dependent in most patients over a 2-week interval: repeating similar doses in patients leads to a decrease of the drug exposure due to a decrease of the half-life and/or to a decrease of the extrapolation to 0 time (intercept parameter). The pharmacokinetics was generally time-independent within a 6-h interval in most patients. During this time interval, the kinetics was not linear: increasing the dose by large proportions does not lead to a proportional increase of drug exposure. This time- and dose-dependence of doxorubicin pharmacokinetics makes it very difficult to monitor the treatments according to the individual pharmacokinetic patterns of patients.

Hepatic extraction, metabolism and biliary excretion of doxorubicin in the isolated perfused rat liver.

The hepatic extraction, metabolism, and biliary excretion of doxorubicin (DX) were studied in the isolated perfused rat liver. Three doses of DX equivalent to 2, 20, and 100 mg/kg in rats were studied over a period of 3 h after bolus injection into the reservoir. DX and metabolites concentration in perfusate, bile, and liver were determined by high-pressure liquid chromatography. The hepatic extraction ratio was low (less than 0.24) and decreased progressively over the 3 h. The hepatic extraction and clearance were significantly lower at the highest dose. Doxorubicinol (DX-OL) was the only metabolite detected in the perfusate, accounting for less than 4% of the total AUC. Thirty-one to thirty-three percent of the dose was excreted into bile over 3 h as unchanged DX. This was reduced to 22% at the highest dose. Only 0.35%-1.33% of the dose was excreted as DX-OL. DX aglycones were found only in the liver, where they represented 20%-30% of the total fluorescence at 3 h. In conclusion, in this model DX has a low extraction ratio, is poorly metabolized and extensively excreted into bile.

[Growth kinetics of paucitransplanted chemically-induced sarcomas]. / Cinétique de croissance de sarcomes chimio-induits paucitransplantés.

We describe a paucitransplanted tumor experimental model. This system shows the advantages of autochtonous and multitransplanted tumors. These paucitransplanted tumors show reduced latency times and slow growth kinetics. In order to determine the maximum number of transplantations above which the specific autochtonous tumor characteristics disappear, the variation of growth kinetics parameters related to the number of transplantations was studied.

[Analysis of the growth kinetics of autochthonous DMBA-induced tumors in mice of various ages and sex]. / Analyse des cinétiques de croissance de tumeurs autochtones induites par le DMBA, chez des souris d'âge et de sexe différents.

In order to understand the kinetics of this experimental model, we studied the influence of age and sex on primary tumoral and pulmonary metastatic yields and on the growth kinetics parameters. Connective tissue tumors were induced by DMBA in male and female Swiss mice of various ages (pre and postpubertal, adult and menopausal). Old mice (induced during the post-menopausal period) show the lowest yield and the slowest growth kinetics. However, prepubertal mice show the highest yield and rapid tumor growth. The characteristics of this experimental model, and particularly the different responsiveness with age, suggest that it may be of value in human preclinical studies.

Hepatic metabolism of doxorubicin in mice and rats.

We have studied the metabolism of doxorubicin in rat and mouse liver, heart and hepatocytes. Doxorubicinol was present in all cases at very low levels and 7-deoxyaglycones were present only in extraphysiological conditions: no aglycones were found either in fresh livers or in hearts of animals treated with the drug, but they were produced in large amounts when the organs were left at room temperature after the death of the animal. Hepatocytes grown in primary cultures or hepatoma cells grown in continuous lines produced no 7-deoxyaglycones. Freshly isolated hepatocytes synthesized small amounts of 7-deoxyaglycones; however, when these hepatocytes were homogenized prior to incubation, high levels of 7-deoxyaglycones were produced. We conclude that 7-deoxyaglycone formation is possible only in injured tissue and is not, therefore, a normal pathway for doxorubicin.

Can taxanes provide benefit in patients with CNS tumors and in pediatric patients with tumors? An update on the preclinical development of cabazitaxel.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: These preclinical data suggest that cabazitaxel could be an effective therapy in CNS and pediatric tumors, supporting ongoing clinical evaluation in these indications.