Summary
Solvent facilitated perfusion (SFP) has been proposed as a technique to increase the delivery of chemotherapeutic agents to tumors. SFP entails direct injection of the agent into the tumor in a water-miscible organic solvent, and because the solvent moves easily through both aqueous solutions and cellular membranes it drives the penetration of the solubilized anticancer agent throughout the tumor. To test this hypothesis, we compared the pharmacokinetics (PK) of 14C-labeled 1,3-bis-chlorethyl-1-nitrosourea (BCNU) in intra-cerebral 9L rat gliomas after intravenous (IV) infusion in 90% saline –10% ethanol or direct intratumoral (IT) injection of 14C-BCNU in 100% ethanol (DTI-015). Treatment with DTI-015 yielded a peak radioactive count (Cmax) for the 14C label that was 100–1000 fold higher in the tumor than in all other tissues in addition to a concentration in the tumor that was 100-fold higher than that achieved following IV infusion of 14C-BCNU. Pathologic and auto-radiographic analysis of tissue sections following IT injection of 14C-BCNU in ethanol into either tumor or normal rat brain revealed both an enhanced local volume of distribution and an increased concentration of BCNU delivered to tumor compared to non-tumor bearing brain. To investigate the mechanism behind the SFP of BCNU to the tumor both dynamic contrast and perfusion MRI were performed on 9L tumors before and after treatment and demonstrated a decrease in tumor perfusion following IT injection of DTI-015. Finally, initial PK of patient blood samples following administration of DTI-015 into relapsed high-grade glioma indicated a 20-fold decrease in systemic exposure to BCNU compared to IV infusion of BCNU providing further evidence for the enhanced therapeutic ratio observed for DTI-015.
Similar content being viewed by others
Abbreviations
- AUC:
-
area under the concentration–time curve
- BCNU:
-
1,3-bis-chlorethyl-1-nitrosourea
- CED:
-
convection enhanced delivery
- Cmax:
-
peak concentration
- CPM:
-
counts per minute
- DTI-015:
-
BCNU prepared in 100% ethanol
- IT:
-
intratumoral
- IV:
-
intravenous
- LD10:
-
the dose of drug which results in death of 10% of the animals due to drug toxicity
- MRI:
-
magnetic resonance imaging
- PK:
-
pharmacokinetics
- SEM:
-
standard error of the mean
- SFP:
-
solvent facilitated perfusion
- t 1/2 :
-
half-life
- TTR:
-
tumor-to-tissue ratio
References
A Behin K Hoang-Xuan AF Carpentier JY Delattre (2003) ArticleTitlePrimary brain tumours in adults Lancet 361 323–331 Occurrence Handle10.1016/S0140-6736(03)12328-8 Occurrence Handle12559880
R Dorr D Hoff (1994) Carmustine R Dorr D Hoffs (Eds) Cancer Chemotherapy Handbook Appleton and Lange Norwalk 267–275
LA Stewart (2002) ArticleTitleChemotherapy in adult high-grade glioma: a systematic review and meta- analysis of individual patient data from 12 randomised trials Lancet 359 1011–1018 Occurrence Handle10.1016/S0140-6736(02)08091-1 Occurrence Handle1:CAS:528:DC%2BD38XisV2htro%3D Occurrence Handle11937180
PS Hasleton BR O’Driscoll P Lynch A Webster SJ Kalra HR Gattamaneini AA Woodcock LW Poulter (1991) ArticleTitleLate BCNU lung: a light and ultrastructural study on the delayed effect of BCNU on the lung parenchyma J Pathol 164 31–36 Occurrence Handle10.1002/path.1711640106 Occurrence Handle1:STN:280:By6B2sjosV0%3D Occurrence Handle2056387
BR O’Driscoll PS Hasleton PM Taylor LW Poulter HR Gattameneni AA Woodcock (1990) ArticleTitleActive lung fibrosis up to 17 years after chemotherapy with carmustine (BCNU) in childhood N Engl J Med 323 378–382 Occurrence Handle1:STN:280:By%2BA3MfksVI%3D Occurrence Handle2370889
GR Thompson RE Larson (1969) ArticleTitleThe hepatotoxicity of 1,3-bis (2-chloroethyl)-1-nitrosurea (BCNU) in rats J Pharmacol Exp Ther 166 104–112 Occurrence Handle1:CAS:528:DyaF1MXns1egsA%3D%3D Occurrence Handle5776013
FH Hochberg AA Pruitt DO Beck G DeBrun K Davis (1985) ArticleTitleThe rationale and methodology for intra-arterial chemotherapy with BCNU as treatment for glioblastoma J Neurosurg 63 876–880 Occurrence Handle1:STN:280:BimD3snks1Y%3D Occurrence Handle2997415
SJ Hassenbusch JH Anderson DM Whiting (1990) ArticleTitleIntra-arterial chemotherapy for brain tumors Cleve Clin J Med 57 513–520 Occurrence Handle1:STN:280:By6D1MfnvVI%3D Occurrence Handle2268962
KA Walter RJ Tamargo A Olivi PC Burger H Brem (1995) ArticleTitleIntratumoral chemotherapy Neurosurgery 37 1128–1145 Occurrence Handle1:STN:280:BymC2MbpsVA%3D Occurrence Handle8584154
H Brem S Piantadosi PC Burger M Walker R Selker NA Vick K Black M Sisti S Brem G Mohr et al. (1995) ArticleTitlePlacebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas The Polymer-brain Tumor Treatment Group. Lancet 345 1008–1012 Occurrence Handle1:STN:280:ByqB2c%2FisVU%3D
BK Kleinschmidt-DeMasters (1986) ArticleTitleIntracarotid BCNU leukoencephalopathy Cancer 57 1276–1280 Occurrence Handle1:STN:280:BimC3szgvFU%3D Occurrence Handle3948112
DF Miller JW Bay RJ Lederman JD Purvis LR Rogers RL Tomsak (1985) ArticleTitleOcular and orbital toxicity following intracarotid injection of BCNU (carmustine) and cisplatinum for malignant gliomas Ophthalmology 92 402–406 Occurrence Handle1:STN:280:BiqC1cbisVA%3D Occurrence Handle2986069
M Westphal DC Hilt E Bortey P Delavault R Olivares PC Warnke IR Whittle J Jaaskelainen Z Ram (2003) ArticleTitleA phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma Neuro-oncol 5 79–88 Occurrence Handle1:CAS:528:DC%2BD3sXjtVKltL4%3D Occurrence Handle12672279
A Olivi SA Grossman S Tatter F Barker K Judy J Olsen J Bruce D Hilt J Fisher S Piantadosi (2003) ArticleTitleDose escalation of carmustine in surgically implanted polymers in patients with recurrent malignant glioma: a new approaches to brain tumor therapy CNS consortium trial J Clin Oncol 21 1845–1849 Occurrence Handle10.1200/JCO.2003.09.041 Occurrence Handle1:CAS:528:DC%2BD2cXpsVWqt7w%3D Occurrence Handle12721262
AB Fleming WM Saltzman (2002) ArticleTitlePharmacokinetics of the carmustine implant Clin Pharmacokinet 41 403–419 Occurrence Handle1:CAS:528:DC%2BD38XlvFKmtbY%3D Occurrence Handle12074689
RH Bobo DW Laske A Akbasak PF Morrison RL Dedrick EH Oldfield (1994) ArticleTitleConvection-enhanced delivery of macromolecules in the brain Proc Natl Acad Sci USA, 91 2076–2080
M Vavra MJ Ali EW Kang Y Navalitloha A Ebert CV Allen DR Groothuis (2004) ArticleTitleComparative pharmacokinetics of 14C-sucrose in RG-2 rat gliomas after intravenous and convection-enhanced delivery Neuro-oncol 6 104–112 Occurrence Handle10.1215/S1152851703000449 Occurrence Handle1:CAS:528:DC%2BD2cXjs1Sqtb0%3D Occurrence Handle15134624
JN Bruce A Falavigna JP Johnson JS Hall BD Birch JT Yoon EX Wu RL Fine AT Parsa (2000) ArticleTitleIntracerebral clysis in a rat glioma model Neurosurgery 46 683–691 Occurrence Handle1:STN:280:DC%2BD3c7ot1Ortg%3D%3D Occurrence Handle10719865
Y Mardor Y Roth Z Lidar T Jonas R Pfeffer SE Maier M Faibel D Nass M Hadani A Orenstein JS Cohen Z Ram (2001) ArticleTitleMonitoring response to convection-enhanced taxol delivery in brain tumor patients using diffusion-weighted magnetic resonance imaging Cancer Res 61 4971–4973 Occurrence Handle1:CAS:528:DC%2BD3MXltVeqtb0%3D Occurrence Handle11431326
SJ Hassenbusch EM Nardone VA Levin N Leeds D Pietronigro (2003) ArticleTitleStereotactic injection of DTI-015 into recurrent malignant gliomas: phase I/II trial Neoplasia 5 9–16 Occurrence Handle1:CAS:528:DC%2BD3sXhs12ltL8%3D Occurrence Handle12659665
D Pietronigro F Drnovsky H Cravioto J Ransohoff (2003) ArticleTitleDTI-015 produces cures in T9 gliosarcoma Neoplasia 5 17–22 Occurrence Handle1:CAS:528:DC%2BD3sXhs12ltLw%3D Occurrence Handle12659666
TL Chenevert PE McKeever BD Ross (1997) ArticleTitleMonitoring early response of experimental brain tumors to therapy using diffusion magnetic resonance imaging Clin Cancer Res 3 1457–1466 Occurrence Handle1:STN:280:DyaK1M7htFSrsg%3D%3D Occurrence Handle9815831
DE Hall BA Moffat J Stojanovska TD Johnson Z Li DA Hamstra A Rehemtulla TL Chenevert J Carter D Pietronnigro BD Ross (2004) ArticleTitleTherapeutic Efficacy of DTI-015 using diffusion MRI as an early surrogate marker Clin Cancer Res 10 7852–7859 Occurrence Handle1:CAS:528:DC%2BD2cXhtVCrs7zL Occurrence Handle15585617
BD Ross H Merkle K Hendrich RS Staewen M Garwood (1992) ArticleTitleSpatially localized in vivo 1H magnetic resonance spectroscopy of an intracerebral rat glioma Magn Reson Med 23 96–108 Occurrence Handle1:STN:280:By2C3s%2FnvFc%3D Occurrence Handle1734186
M Colvin RB Brundrett W Cowens I Jardine DB Ludlum (1976) ArticleTitleA chemical basis for the antitumor activity of chloroethylnitrosoureas Biochem Pharmacol 25 695–699 Occurrence Handle10.1016/0006-2952(76)90246-X Occurrence Handle1:CAS:528:DyaE28XkslajtrY%3D Occurrence Handle945062
VT DeVita C Denham JD Davidson VT Oliverio (1967) ArticleTitleThe physiological disposition of the carcinostatic 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in man and animals Clin Pharmacol Ther 8 566–577 Occurrence Handle1:CAS:528:DyaF2sXkslagurs%3D Occurrence Handle4951973
VA Levin W Hoffman RJ Weinkam (1978) ArticleTitlePharmacokinetics of BCNU in man: a preliminary study of 20 patients Cancer Treat Rep 62 1305–1312 Occurrence Handle1:STN:280:CSaD3c7ntVc%3D Occurrence Handle688274
BD Ross YJ Zhao ER Neal LD Stegman M Ercolani O Ben-Yoseph TL Chenevert (1998) ArticleTitleContributions of cell kill and posttreatment tumor growth rates to the repopulation of intracerebral 9L tumors after chemotherapy: an MRI study Proc Natl Acad Sci USA, 95 7012–7017
TL Chenevert LD Stegman JM Taylor PL Robertson HS Greenberg A Rehemtulla BD Ross (2000) ArticleTitleDiffusion magnetic resonance imaging: an early surrogate marker of therapeutic efficacy in brain tumors J Natl Cancer Inst 92 2029–2036 Occurrence Handle10.1093/jnci/92.24.2029 Occurrence Handle1:STN:280:DC%2BD3M3jt1eisQ%3D%3D Occurrence Handle11121466
WJ Bodell DD Giannini S Singh D Pietronigro VA Levin (2003) ArticleTitleFormation of DNA adducts and tumor growth delay following intratumoral administration of DTI-015 J Neurooncol 62 251–258 Occurrence Handle10.1023/A:1023383717833 Occurrence Handle12777076
WJ Bodell DD Giannini S Hassenbusch VA Levin (2001) ArticleTitleLevels of N7-(2-hydroxyethyl)guanine as a molecular dosimeter of drug delivery to human brain tumors Neuro-oncol 3 241–245 Occurrence Handle10.1215/S1522851701000035 Occurrence Handle1:CAS:528:DC%2BD38Xks1Olsro%3D Occurrence Handle11584893
L Simpson-Herren D Pietronigro (1999) Intratumoral injection of DTI-015 in the Walker 256 subcutaneous model Proc Am Assoc Cancer Res 583 pp
BD Ross TL Chenevert B Kim O Ben-Yoseph (1994) ArticleTitleMagnetic resonance imaging and spectroscopy: application to experimental neuro-oncology Q Magn Reson Biol Med 1 89–106
RD Fross PC Warnke DR Groothuis (1991) ArticleTitleBlood flow and blood-to-tissue transport in 9L gliosarcomas: the role of the brain tumor model in drug delivery research J Neurooncol 11 185–197 Occurrence Handle10.1007/BF00165526 Occurrence Handle1:STN:280:By2A2szivVU%3D Occurrence Handle1823340
RG Steen MM Graham (1991) ArticleTitle31P magnetic resonance spectroscopy is sensitive to tumor hypoxia: perfusion and oxygenation of rat 9L gliosarcoma after treatment with BCNU NMR Biomed 4 117–124 Occurrence Handle1:STN:280:By2D3c7hsVA%3D Occurrence Handle1911098
Moffat B, Chenevert T, Hall D, Rehemtulla A, Ross B: Quantitative perfusion imaging by continuous inversion using pulse trained arterial spin labeling. J Magn Reson Imaging, in press
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hamstra1, D.A., Moffat, B.A., Hall, D.E. et al. Intratumoral injection of BCNU in ethanol (DTI-015) results in enhanced delivery to tumor – a pharmacokinetic study. J Neurooncol 73, 225–238 (2005). https://doi.org/10.1007/s11060-004-5675-2
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s11060-004-5675-2