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PDF file - 51KB, Body weights of MDA-MB-231 bearing mice treated with E-3810, 5FU, DDP and their combinations.

PDF file - 63KB, Circulating factors in plasma of mice bearing MDA-MB-231 tumors untreated or treated with E-3810 (E), brivanib (B), sunitinib (S), paclitaxel (PTX) and their combinations as described in Material amd Methods.

PDf file - 30KB, Survival curves of MDA-MB-231 bearing mice treated with E-3810, PTX and their combination.

PDF file - 41KB, Dose response curve of PTX in MDA-MB-231 cells alone or in combination with E-3810, sunitinb and brivanib.

PDF file - 101KB

Supplementary Table 1 from E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models

Supplementary Figures 1-4 from E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models

Supplementary Table 2 from E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models

Supplementary Methods, Figure Legends 1-4 from E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models

Tumor angiogenesis is a degenerate process regulated by a complex network of proangiogenic factors. Existing antiangiogenic drugs used in clinic are characterized by selectivity for specific factors. Antiangiogenic properties might be improved in drugs that target multiple factors and thereby address the inherent mechanistic degeneracy in angiogenesis. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) family members and their cognate receptors are key players in promoting tumor angiogenesis. Here we report the pharmacologic profile of E-3810, a novel dual inhibitor of the VEGF and FGF receptors. E-3810 potently and selectively inhibited VEGF receptor (VEGFR)-1, -2, and -3 and FGF receptor (FGFR)-1 and -2 kinases in the nanomolar range. Ligand-dependent phosphorylation of VEGFR-2 and FGFR-1 was suppressed along with human vascular endothelial cell growth at nanomolar concentrations. In contrast, E-3810 lacked cytotoxic effects on cancer cell lines under millimolar concentrations. In a variety of tumor xenograft models, including early- or late-stage subcutaneous and orthotopic models, E-3810 exhibited striking antitumor properties at well-tolerated oral doses administered daily. We found that E-3810 remained active in tumors rendered nonresponsive to the general kinase inhibitor sunitinib resulting from a previous cycle of sunitinib treatment. In Matrigel plug assays performed in nude mice, E-3810 inhibited basic FGF–induced angiogenesis and reduced blood vessel density as assessed by histologic analysis. Dynamic contrast-enhanced magnetic resonance imaging analysis confirmed that E-3810 reduced the distribution of angiogenesis-sensitive contrast agents after only 5 days of treatment. Taken together, our findings identify E-3810 as a potent antiangiogenic small molecule with a favorable pharmacokinetic profile and broad spectrum antitumor activity, providing a strong rationale for its clinical evaluation. Cancer Res; 71(4); 1396–405. ©2011 AACR.

Protein kinases are one of the largest known families of enzyme characterized by having a well conserved ATP binding pocket. Most of the synthetic kinase inhibitors are ATP-competitive, but display some potential problems, like selectivity, discrepancy between the in vitro and in vivo inhibition assays and an high risk of developing mutation inside the ATP-binding pocket. Recently some new inhibitors with a non-competitive mechanism of action were reported, with intresting results both in vitro and in vivo.

Pixantrone is an immunesuppressor similar to mitoxantrone but with lower cardiotoxicity. We evaluated the effect of pixantrone on B cells and lymphomononuclear cells in the course of acute EAE. Pixantrone reduced the number of B cells and suppressed myelin basic protein (MBP) specific IgG production. In vitro, pixantrone induced apoptosis of rat B lymphocytes in a way similar to mitoxantrone. In addition, pixantrone inhibited antigen specific and mitogen induced lymphomononuclear cell proliferation, as well as IFN-γ production, during EAE. These findings suggest a similar mechanism of action for pixantrone and mitoxantrone on the effector function of lymphomonocyte B and T cells.

With the aim to provide second-generation anthracenedione analogues endowed with reduced side effects and a wider spectrum of action than mitoxantrone and doxorubicin, a large number of new molecules bearing nitrogen atoms in the chromophore was synthesized and screened in vitro and in vivo. From this screening, BBR 2778 (6,9-bis[(2-aminoethyl)amino] benzo[g]isoquinoline-5,10-dione dimaleate) emerged as the most interesting compound. BBR 2778 was tested in vitro on several murine and human tumor cell lines and showed cytotoxic potency lower than that of mitoxantrone and doxorubicin. BBR 2778 was more cytotoxic in leukemia and lymphoma cell lines than in solid tumor cell lines. Although against in vivo models BBR 2778 was less potent than mitoxantrone and doxorubicin, its antitumor activity was equal or superior (in certain tumor models) to that of the above standard compounds. In particular, BBR 2778 was curative against L1210 murine leukemia and YC-8 murine lymphoma. Moreover, it showed an antitumor activity comparable to that of mitoxantrone and doxorubicin on solid tumors. No cardiotoxic effect of BBR 2778 in animals not pretreated with anthracyclines was observed compared to standards. In light of its spectrum of activity and marked efficacy against lymphomas and leukemias over a wide dose range, together with its lack of delayed cardiotoxicity, BBR 2778 has been entered in clinical studies.

The issue of dimethylsulfoxide (DMSO) neurotoxicity is an important one, given its wide use in experimental toxicology as a solvent for hydrophobic substances. We examined the effect of the intraperitoneal administration of different DMSO solutions (1.8-7.2%) on the peripheral nervous system of Wister rats treated for 10 consecutive days and followed-up for an additional 45 days. DMSO administration induced a dose-dependent reduction in nerve conduction velocity, with complete recovery occurring in the follow-up. No structural changes were found in the sciatic nerve at 1.8%, and 3.6% DMSO concentrations, suggesting that the mechanism of action of DMSO involves a functional impairment (i.e. conduction block) similar to that already described for this substance in isolated systems. However, when DMSO was administered at the 7.2% concentration, evident structural changes were observed in the sciatic nerve, with myelin disruption and uncompacted myelin lamalle. The neurophysiological and pathological changes observed in our study are severe enough to merit careful consideration in the course of experimental studies involving DMSO as a solvent for drugs which are under evaluation For their potential neurotoxicity. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.

E-3810 is a novel small molecule that inhibits VEGF receptor-1, -2, and -3 and fibroblast growth factor receptor-1 tyrosine kinases at nmol/L concentrations currently in phase clinical II. In preclinical studies, it had a broad spectrum of antitumor activity when used as monotherapy in a variety of human xenografts. We here investigated the activity of E-3810 combined with different cytotoxic agents in a MDA-MB-231 triple-negative breast cancer xenograft model. The molecule could be safely administered with 5-fluorouracil, cisplatin, and paclitaxel. The E-3810–paclitaxel combination showed a striking activity with complete, lasting tumor regressions; the antitumor activity of the combination was also confirmed in another triple-negative breast xenograft, MX-1. The activity was superior to that of the combinations paclitaxel+brivanib and paclitaxel+sunitinib. Pharmacokinetics studies suggest that the extra antitumor activity of the combination is not due to higher paclitaxel tumor levels, which in fact were lower in mice pretreated with all three kinase inhibitors, and the paclitaxel plasma levels excluded reduced drug availability. Pharmacodynamic studies showed that E-3810, brivanib, and sunitinib given as single agents or in combination with paclitaxel reduced the number of vessels, but did not modify vessel maturation. Reduced tumor collagen IV and increased plasma collagen IV, associated with increased matrix metalloproteinases (MMP), particularly host MMP-9, indicate a proteolytic remodeling of the extracellular matrix caused by E-3810 that in conjunction with the cytotoxic effect of paclitaxel on the tumor cells (caspase-3/7 activity) may contribute to the striking activity of their combination. These data support the therapeutic potential of combining E-3810 with conventional chemotherapy. Mol Cancer Ther; 12(2); 131–40. ©2012 AACR.

Background Although Huntington’s disease (HD) is not typically considered a mitochondrial disorder, many studies suggest mitochondrial dysfunction as one of the major player in its pathogenesis and candidate it as molecular target for the development of valuable therapeutic treatments for the disease. So far, several mitochondrial-based therapeutic strategies have been designed either at preclinical or at clinical levels, however none of them has been significantly successful. Aims The purpose of this study was to elucidate the putative role and the mechanistic relevance as well as the validity of dysfunctional mitochondrial permeability transition pore (mPTP) in the pathogenesis of HD with the ultimate aim to clarify whether its modulation might represent a real alternative therapeutic approach for the treatment of this disease. In particular, we investigated whether the administration of GNX-4728, an mPTP inhibitor, already examined in a mouse model of ALS, might be beneficial also in HD. Methods Anti-apoptotic property of GNX-4728 was explored in a mouse striatal-derived cell model (STHdh) expressing endogenous levels of wild type (STHdh7/7) or mutant (STHdh111/111) Huntingtin. The apoptotic profile and the activation of pro-survival pathways, with or without GNX-4728, was assessed by Annexin V staining and Western Blotting, respectively. Results Our findings demonstrated that administration of GNX-4728 significantly reduced apoptosis in HD cells. Such a beneficial effect was associated with ameliorated mitochondrial homeostasis and activation of pro-survival Akt and ERK1/2 signalling pathways. Conclusions Our results strongly support the hypothesis that mPTP may represent a valuable therapeutic target for the development of new and more effective treatment against neuronal dysfunction and cell death occurring in HD.

Anthracyclines and anthracenediones are important oncotherapeutics; however, their use is associated with irreversible and cumulative cardiotoxicity. A novel aza-anthracenedione, pixantrone (BBR 2778), was developed to reduce treatment-related cardiotoxicity while retaining efficacy. This study evaluates the cumulative cardiotoxic potential of pixantrone compared with equiactive doses of doxorubicin and mitoxantrone in both doxorubicin-pretreated and doxorubicin-naive mice. CD1 female mice were given doxorubicin 7.5 mg/kg (once weekly for 3 weeks) followed 6 weeks later by either sterile 0.9% saline, doxorubicin 7.5 mg/kg, pixantrone 27 mg/kg, or mitoxantrone 3 mg/kg (once weekly for 3 weeks). A second group of CD1 female mice were given 2 cycles of either sterile 0.9% saline, pixantrone 27 mg/kg, doxorubicin 7.5 mg/kg, or mitoxantrone 3 mg/kg (once weekly for 3 weeks). Animals were sacrificed at different time points for histopathologic examination of the heart. In the doxorubicin-pretreated mice, further exposure to doxorubicin or mitoxantrone resulted in a significant worsening of pre-existing degenerative cardiomyopathy. In contrast, pixantrone did not worsen pre-existing cardiomyopathy in these animals. Only minimal cardiac changes were observed in mice given repeated cycles of pixantrone, while 2 cycles of doxorubicin or mitoxantrone resulted in marked or severe degenerative cardiomyopathy. These animal studies demonstrate the reduced cardiotoxic potential of pixantrone compared with doxorubicin and mitoxantrone. Exposure to pixantrone did not worsen pre-existing cardiomyopathy in doxorubicin-pretreated mice, suggesting that pixantrone may be useful in patients pretreated with anthracyclines.

Pixantrone is less cardiotoxic and is similarly effective to mitoxantrone (MTX) as an antineoplastic drug. In our study, pixantrone reduced the severity of acute and decreased the relapse rate of chronic relapsing experimental allergic encephalomyelitis (EAE) in rats. A marked and long-lasting decrease in CD3+, CD4+, CD8+ and CD45RA+ blood cells and reduced anti-MBP titers were observed with both pixantrone and MTX. In vitro mitogen- and antigen-induced T-cell proliferation tests of human and rodents cells evidenced that pixantrone was effective at concentrations which can be effectively obtained after i.v. administration in humans. Cardiotoxicity was present only in MTX-treated rats. The effectiveness and the favorable safety profile makes pixantrone a most promising immunosuppressant agent for clinical use in multiple sclerosis (MS).

E-3810 is a small molecule inhibitor of VEGFR-1, -2 and -3 and FGFR-1 tyrosine kinases with IC50 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C192.

E-3810 is a novel small molecule that selectively inhibits VEGF receptor-1, -2 and -3 and FGF receptor-1 (FGFR-1) tyrosine kinases currently undergoing a Phase 1 clinical trial in Europe. We have previously shown that the compound has strong anti-angiogenic effects in vivo and displays potent activity in all the human xenograft models in which it has been tested. We have also recently demonstrated that interference with FGF/FGFR pathway could result in a higher drug cytotoxic activity in those cell lines whose growth in vitro was dependent on the pathway. In order to corroborate these findings in an in vivo setting, a panel of human xenografts characterized by different expression of FGFR-1and FGF2 ligand is being screened for the response to E-3810 given at its optimal dose (20 mg/kg per os daily). Athymic female mice were transplanted s.c. with the different human xenografts and, when tumor masses reached the size of 80-120 mg, were randomized to receive vehicle or E-3810 for 14 days. Results are available for 7 models (see table reported below). All the selected tumors displayed similar growth rates, except for RXF_486 that grew more slowly. Tumor growth resumed upon drug withdrawal, at a rate seemingly higher where FGFR-1 was highly expressed. These preliminary results confirm the strong activity of E-3810 in a large panel of tumours, with growth control and, sometimes, regressions. Studies are ongoing to enlarge the panel of models and to confirm the observed trend suggesting a somewhat higher sensitivity to E-3810 in tumors expressing higher FGFR-1 and\or FGF ligand. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 595. doi:10.1158/1538-7445.AM2011-595

E-3810 is a novel small molecule that selectively inhibits VEGFR-1, -2 and -3 and FGFR-1 tyrosine kinases with IC50 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2574. doi:10.1158/1538-7445.AM2011-2574

Background: E-3810 is a potent VEGFR1, 2 and 3 and FGFR 1 kinases inhibitor showing potent anti-angiogenic and antitumor activity in several in vitro and in vivo mouse models (Proceedings AACR-EORTC-NCI Meeting, Boston, November 2009; Abstracts No. 252 and 257). The aim of this study was to investigate, in a rat model, the antitumor activity of E-3810 and its anti-angiogenic effects by using DCE-MRI and to correlate the response with a panel of biological markers. Methods: Nude rats were subcutaneously xenografted with human Calu-6 lung cancer cells and treated orally once daily for 14 consecutive days, either with E-3810 − 10 mpk (dose chosen on the basis of a preliminary study in the same model) or Sorafenib − 100 mpk. Tumor growth and parameters reflecting tumor vascular permeability/perfusion (Ktrans) were evaluated by T2-weighted MRI and by T1-weighted DCE-MRI using Gd-DTPA (Magnevist®) as contrast agent at D-1, D1, D3, D7 and D14. The number, maturity and functionality of tumor vessels were assessed using CD31/α-SMA colocalisation by IHC and injection of Hoechst fluorescent dye on D1, D3, D7 and D14. On the same days, the level of circulating endothelial cells (CEC) and collagen IV were measured by FACS and ELISA assays. Results: In comparison to vehicle-treated animals, a marked tumor growth inhibition was observed in E-3810-treated rats (max T/C 21%) with no remarkable signs of toxicity. In the same animals, Ktrans value in the tumor rim was significantly decreased (up to 49% on D14). This DCE-MRI finding was supported by the significant decrease in the Hoechst stained area observed at D1 (−97%), D7 (−96%) and D14 (−75%). In addition, the number of tumor vessels (both CD31 and colocalized CD31/α-SMA) was significantly decreased at D3 (−72%), D7 (−68%) and D14 (−86%) in E-3810-treated rats. Always in comparison to vehicle group, no significant changes in CEC were observed after treatment with E-3810, whereas collagen IV levels significantly increased at D14 (+38). Similar effects on all the above mentioned parameters were observed in Sorafenib treated animals. Conclusions: E-3810 displayed a marked antitumor activity in the model of Calu-6 tumor bearing nude rats. The antitumor effect is coupled with a strong antiangiogenic activity, as indicated by decrease in vascular permeability/perfusion and decrease of microvessels density that occur early on and are maintained throughout the treatment period. 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 1367.

E-3810, 6-[[7-[(1-aminocyclopropyl)methoxy]-6-methoxy-4-quinolyl]oxy]-N-methyl-naphthalene-1-carboxamide, is a novel small molecule that potently and selectively inhibits VEGFR1-3 and FGFR-1 tyrosine kinases. E-3810 has shown antitumor activity against various types of cancer xenografts with good tolerability. The anti-angiogenic proprieties of E-3810 were investigated in vitro on endothelial cells and in vivo in angiogenesis-induced models and human tumor xenografts. E-3810 inhibited VEGF- and FGF-2-induced HUVEC (human umbilical vein endothelial cells) proliferation with an IC50 of 40–50 nM. The ability of E-3810 to inhibit angiogenesis in vivo was assessed in the Matrigel plug assay, where angiogenesis is induced by FGF-2 embedded in Matrigel pellets, implanted subcutaneously in mice. Treatment with E-3810 (20 mg/kg p.o., daily for 6 days) completely inhibited the angiogenic response measured by hemoglobin content. The effect on tumor angiogenesis was investigated in the human A498 renal carcinoma xenografted subcutaneously in nude mice. Oral treatment with E-3810 for up 30 days at the optimal antitumor dose of 20 mg/kg led to significant tumor growth delay (Treated -Controls = 24 days). E-3810 significantly decreased blood vessel density and increased vessel maturation index (assessed by immunostaining with anti CD31 and CD31/ SMA antibodies); this was accompanied by decreased expression of stroma collagen IV and increased tumor necrosis. A498 xenografts growing in nude mice were also analyzed by DCE-MRI (dynamic contrast-enhanced magnetic resonance imaging) before and after 5 and 12 days of oral treatments with 20 mg/kg E- 3810. The kinetic analysis of the distribution of the contrast agent (Gadocoletic Acid Trisodium Salt, B22956/1, Bracco S.p.a., Italy) showed significant reduction in perfusion, calculated applying the IAUC method over the first 30 minutes post contrast injection, in E-3810 treated tumors compared with both baseline values and untreated controls already after 5 days of treatment. These results show a significant antiangiogenic activity of E-3810, which is likely to contribute to its potent antitumor activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A262.

E-3810, 6-[[7-[(1-aminocyclopropyl)methoxy]-6-methoxy-4-quinolyl]oxy]-N-methyl-naphthalene-1-carboxamide, is a novel small molecule that potently and selectively inhibits VEGFR1-3 and FGFR-1 tyrosine kinases (TKs) with IC50 in the 10-20 nM range. Concentrations at least 1-order higher were required to inhibit FGFR-2 and 3, PDGFRα and β and c-Kit receptors and no relevant activity was seen against different cancer-related TKs. E-3810 1-10 nM inhibited the ligand-dependent phosphorylation of VEGFR-2 and FGFR-1 and the downstream phosphorylation of Erk in HUVEC cells; inhibition of PDGFR- auto-phosphorylation in NIH-3T3 cells was detected at concentrations higher than 100 nM. E-3810 inhibited the VEGF- and FGF-driven growth of HUVEC cells (IC50 40-50 nM), while anti-proliferative activity on different human cancer cell lines was shown at 10-30 M concentrations. E-3810 was tested in different human tumor xenografts in nude mice, including colon HT-29, ovarian A-2780, renal A498, RXF393 and SKN12I carcinomas. A dose dependent antitumor effect was observed in a range from 10 to 40 mg/kg given orally for 30 consecutive days. The optimal dose schedule, 20 mg/kg for 30 days, was well tolerated and caused up to 90% suppression of tumor growth. Sustained growth inhibition was also seen when treatment was repeated after a 2-week dosing interval or when dosing was initiated at a larger tumor volume (average 400 mm3). Tumor regression was observed in the RXF393 xenograft. E-3810 showed antitumor activity equal or better than Sunitinib and Brivanib at their respective optimal doses. Pharmacokinetic studies in mice demonstrated high oral bioavailability, high volume of distribution and terminal half life of 4 hrs. After single and repeated administration E-3810 systemic exposure was proportional to the dose, without any accumulation after repeated doses. The good bioavailability and the remarkable antitumor activity of E-3810 in several tumor xenografts make this compound an interesting candidate for clinical development. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A257.

Reduced glutathione has been shown to be an effective protector against cisplatin-induced nephrotoxicity of potential clinical value, since it does not reduce antitumor activity of the cytotoxic drug. This paper extends previous observations on the protective potential of reduced glutathione against cisplatin-induced nephrotoxicity, in different rodent models. Following i.v. administration, glutathione protection against cisplatin-induced nephrotoxicity was found to be critically dependent on timing of thiol administration. Whereas the sulfhydryl compound provided almost complete protection in CD rats, the protective effect against toxic renal damage was only partial in mice of different strains. In spite of the modest protection against kidney toxicity, glutathione reduced lethal toxicity in the mouse. Under the same experimental conditions at protective dose levels, the tripeptide thiol did not interfere with the antitumor effectiveness of cisplatin, in any of the tumor models examined. The kidney content of non-protein sulphydryls of CD rats produced by the effective dose of glutathione was markedly higher than that found in the mouse treated with the same dose. This finding is consistent with a differential protection provided by glutathione against cisplatin-induced renal toxicity in these species.

Pretreatment of Swiss mice and Sprague-Dawley rats with glutathione (GSH) reduced the acute lethal toxicity of cis-dichlorodiammine platinum (II) (cis-DDP) in a dose-dependent manner. The protection was accompanied by reduction of both body weight loss and by reduction of nephrotoxicity, as measured by a rise in serum blood urea nitrogen (BUN), creatinine levels and by histopathologic changes, which occurred 4 days following cis-DDP treatment. The antitumor effects of cis-DDP on experimental tumor models (P388 and Gross leukemia) were not significantly altered by GSH treatment. It is suggested that the partial protection by GSH from acute toxicity of the antitumor drug is directly related to protection of renal function.

Since the usefulness of high-dose cyclophosphamide is often limited by hemorrhagic cystitis, and the use of sulfhydryl-containing compounds prevents this side effect, this study was carried out to compare the uroprotective efficacy of 2-mercaptoethane sulfonate (MESNA) with that of reduced glutathione. In experimentally cyclophosphamide-induced urotoxicity in mice, the protective efficacy and potency of these thiols were similar, since both agents afforded complete protection in the same dose range. This finding suggests that these compounds are suitable sources of urinary thiols. Although the rationale for the clinical use of these protectors is similar, glutathione may have therapeutic advantages over MESNA because of a wider margin of safety and multiple protective actions displayed by the tripeptide thiol.

The effect of reduced glutathione on acute lethal toxicity and urotoxicity induced by cyclophosphamide was studied on both mice and rats. The results of this investigation indicate that reduced glutathione is an effective protective agent against bladder damage from treatment with the alkylating agent. The timing of glutathione administration (IV) with respect to cyclophosphamide treatment influenced the uroprotective efficacy of the thiol compound. A schedule-dependent protective effect of glutathione against acute lethal toxicity of the antitumor drug was also observed. This partial protection was accompanied by a reduction in body weight loss following cyclophosphamide treatment. The therapeutic activity of cyclophosphamide on two experimental tumor systems (L1210 and Gross leukemia) was not impaired by combined treatment with glutathione, even at a relatively high dose of glutathione compared with cyclophosphamide.

The distribution of paclitaxel (Taxol(R) within the central and peripheral nervous system after repeated administration of this antineoplastic agent is still largely unknown. In this study we determined for the first time paclitaxel tissue concentration in the brain, spinal cord, dorsal root ganglia (DRG) and sciatic nerve using an experimental paradigm in the rat which reproduces the features of paclitaxel peripheral neurotoxicity in humans. Pathological confirmation of the onset of paclitaxel-induced peripheral neurotoxicity was performed. In order to achieve reliable results even with low concentrations of paclitaxel, a newly reported analytical method thigh-performance liquid chromatography with tandem mass spectrometry) was used. We demonstrated that paclitaxel has easy access to the DRG, where it accumulates, while the lowest concentrations of the drug were measured in the brain. The intermediate concentrations of paclitaxel observed in the sciatic nerve and spinal cord may be due to paclitaxel transport along the centrifugal and centripetal branches of the DRG neuron axons. (C) 2000 Intox Press, Inc.