|
|
|
|
|
|
||
|
|
||||
|
|
||||
|
||||
Preclinical Experimental Therapeutics |
Bill Walsh Cancer Research Laboratories, Royal North Shore Hospital, Sydney, NSW 2065, Australia (F.M.B.); Sidney Kimmel Cancer Center at Johns Hopkins Medical Center, Baltimore, MD 21231, USA (S.L.E., S.A.G.)
3 Address correspondence to Frances M. Boyle, Department of Medical Oncology, Royal North Shore Hospital, Pacific Highway, St. Leonards, Sydney, 2065 Australia (franb{at}bigpond.net.au).
Abstract
Vincristine is an integral part of the "PCV" regimen that is commonly administered to treat primary brain tumors. The efficacy of vincristine as a single agent in these tumors has been poorly studied. This study was designed to determine whether vincristine enters normal rat brain or an intracranially or subcutaneously implanted glioma and to assess the presence of the efflux pump P-glycoprotein (P-gp) on tumor and vascular endothelial cells. The 9L rat gliosarcoma was implanted intracranially and subcutaneously in three Fischer 344 rats. On day 7, [3H]vincristine (50 µCi, 4.8 µg) was injected into the carotid artery, and the animals were euthanized 10 or 20 min later. Quantitative autoradiography revealed that vincristine levels in the liver were 6- to 11-fold greater than in the i.c. tumor, and 15- to 37-fold greater than in normal brain, the reverse of the expected pattern with intra-arterial delivery. Vincristine levels in the s.c. tumor were 2-fold higher than levels in the i.c. tumor. P-gp was detected with JSB1 antibody in vascular endothelium of both normal brain and the i.c. tumor, but not in the tumor cells in either location, or in endothelial cells in the s.c. tumor. These results demonstrate that vincristine has negligible penetration of normal rat brain or i.c. 9L glioma despite intra-arterial delivery and the presence of blood-brain barrier dysfunction as demonstrated by Evan's blue. Furthermore, this study suggests that P-gp-mediated efflux from endothelium may explain these findings. The lack of penetration of vincristine into brain tumor and the paucity of single-agent activity studies suggest that vincristine should not be used in the treatment of primary brain tumors.
References
Bauman, G.S., and Cairncross, J.G. (2001) Multidisciplinary management of adult anaplastic oligodendrogliomas and anaplastic mixed oligo-astrocytomas. Semin. Radiat. Oncol. 11,170 -180.[CrossRef][ISI][Medline]
Buckner, J.C., Gesme, D., Jr., O'Fallon, J.R., Hammack, J.E.,
Stafford, S., Brown, P.D., Hawkins, R., Scheithauer, B.W., Erickson, B.J.,
Levitt, R., Shaw, E.G., and Jenkins, R. (2003) Phase II trial of
procarbazine, lomustine, and vincristine as initial therapy for patients with
low-grade oligodendroglioma or oligoastrocytoma: Efficacy and associations
with chromosomal abnormalities. J. Clin. Oncol.
21,251
-255.
Castle, M.C., Margileth, D.A., and Oliverio, V.T.
(1976) Distribution and excretion of (3H)vincristine in the rat
and the dog. Cancer Res.
36,3684
-3689.
Collins, J.M. (1984) Pharmacological rationale for regional drug delivery. J. Clin. Oncol. 2, 498-504.[Abstract]
El Dareer, S.M., White, V.M., Chen, F.P., Mellet, L.B., and Hill, D.L. (1977) Distribution and metabolism of vincristine in mice, rats, dogs, and monkeys. Cancer Treatment Rep. 61,1269 -1277.[ISI][Medline]
Fetell, M.R., Grossman, S.A., Fisher, J.D., Erlanger, B., Rowinsky, E., Stockel, J., and Piantadosi, S. (1997) Preirradiation paclitaxel in glioblastoma multiforme: Efficacy, pharmacology, and drug interactions. J. Clin. Oncol. 15,3121 -3128.[Abstract]
Fewer, D., Wilson, C.B., Boldrey, E.B., Enot, K.J., and Powell, M.R. (1972) The chemotherapy of brain tumors: Clinical experience with carmustine (BCNU) and vincristine. JAMA 222,549 -552.[CrossRef][Medline]
Fine, R.L., Morgan, P.F., Hsieh, A.-L., Boncek, V., and Durcan, M.J. (1996) Inhibition of P-glycoprotein (Pgp) in the intact blood-brain barrier (BBB) leads to increased penetration of Navelbine (vinorelbine) into the brain. Proc. Am. Assoc. Cancer Res. 37,290 (Abstract #1970).
Gidding, C.E., Kellie, S.J., Kamps, W.A., and de Graaf, S.S. (1999) Vincristine revisited. Crit. Rev. Oncol. Hematol. 29,267 -287.[ISI][Medline]
Gilbert, M.R., Supko, J.G., Batchelor, T., Lesser, G., Fisher,
J.D., Piantadosi, S., and Grossman, S. (2003) Phase I clinical
and pharmacokinetic study of irinotecan in adults with recurrent malignant
glioma. Clin. Cancer Res.
9,2940
-2949.
Greig, N.H., Soncrant, T.T., Shetty, H.U., Momma, S., Smith, Q.R., and Rapoport, S.I. (1990) Brain uptake and anticancer activities of vincristine and vinblastine are restricted by their low cerebrovascular permeability and binding to plasma constituents in rat. Cancer Chemother. Pharmacol. 26,263 -268.[CrossRef][ISI][Medline]
Grossman, S.A., Hochberg, F., Fisher, J., Chen, T.L., Kim, L., Gregory, R., Grochow, L.B., and Piantadosi, S. (1998) Increased 9–aminocamptothecin dose requirements in patients on anticonvulsants. NABTT CCNS Consortium. The New Approaches to Brain Tumor Therapy. Cancer Chemother. Pharmacol. 42,118 -126.[CrossRef][ISI][Medline]
Hilkens, P.H.E., and van den Bent, M.J. (1997) Chemotherapy-induced peripheral neuropathy. J. Peripher. Nerv. Syst. 2,350 -361.[Medline]
Kimmler, B.F. (1994) The 9L rat brain tumor model for pre-clinical investigation of radiation-chemotherapy interactions. J. Neurooncol. 20,103 -109.[Medline]
Kristof, R.A., Neuloh, G., Hans, V., Dickert, M., Urbach, H., Schlegel, U., Simon, M., and Schramm, J. (2002) Combined surgery, radiation, and PCV chemotherapy for astrocytomas compared to oligodendrogliomas and oligoastrocytomas WHO grade III. J. Neurooncol. 59,231 -237.[CrossRef][Medline]
Lassman, L.P., Pearce, G.W., and Gang, J. (1965) Sensitivity of intracranial gliomas to vincristine sulphate. Lancet, Feb. 6,296 -298.
Lassman, L.P., Pearce, G.W., and Gang, J. (1966) Effect of vincristine sulphate on the intracranial gliomata of childhood. Br. J. Surg. 53,774 -777.[Medline]
Levin, V.A., Silver, P., Hannigan, J., Wara, W. M., Gutin, P.H., Davis, R.L., and Wilson, C.B. (1990) Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int. J. Radiat. Oncol. Biol. Phys. 18,321 -324.[ISI][Medline]
Levin, V.A., Yung, W.K., Bruner, J., Kyritsis, A., Leeds, N., Gleason, M.J, Hess, K.R., and Meyers, C.A. (2002) Phase II study of accelerated fractionation radiation therapy with carboplatin followed by PCV chemotherapy for the treatment of anaplastic gliomas. Int. J. Radiat. Oncol. Biol. Phys. 53,58 -66.[Medline]
Louis, E., Keime-Guibert, F., Delattre, J.-Y., and Sanson, M.
(2003) Dramatic response to chemotherapy in oligodendroglial
gliomatosis cerebri. Neurology
60, 151.
Medical Research Council Brain Tumor Working Party
(2001) Randomized trial of procarbazine, lomustine, and
vincristine in the adjuvant treatment of high-grade astrocytoma: A Medical
Research Council trial. J. Clin. Oncol.
19,509
-518.
Murphy, C., Pickles, T., Knowling, M., and Thiesse, B. (2002) Concurrent modified PCV chemotherapy and radiotherapy in newly diagnosed grade IV astrocytoma. J. Neurooncol. 57,215 -220.[CrossRef][Medline]
Nabors, M.W., Griffin, C.A., Zehnbauer, B.A., Hruban, R.H., Phillips, P.C., Grossman, S.A., Brem, H., and Colvin, O.M. (1991) Multidrug resistance gene (MDR1) expression in human brain tumors. J. Neurosurg. 75,941 -946.[Medline]
Prados, M.D., Scott, C., Curran, W.J., Jr., Nelson, D.F., Leibel,
S., and Kramer, S. (1999) Procarbazine, lomustine, and
vincristine (PCV) chemotherapy for anaplastic astrocytoma: A retrospective
review of Radiation Therapy Oncology Group protocols comparing survival with
carmustine or PCV adjuvant chemotherapy. J. Clin.
Oncol. 17,3389
-3395.
Ron, I.G., Gal, O., Vishne, T.H., and Kovner, F. (2002) Long-term follow-up in managing anaplastic astrocytoma by multimodality approach with surgery followed by postoperative radiotherapy and PCV-chemotherapy: Phase II trial. Am. J. Clin. Oncol. 25,296 -302.[Medline]
Schinkel, A.H., Smit, J.J., van Tellingen, O., Beijnen, J.H., Wagenaar, E., van Deemter, L., Mol, C.A.A.M., van der Valk, M.A., Robanus-Maandag, E.C., te Riele, H.P.J., Berns, A.J.M., and Borst, P. (1994) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and increased sensitivity to drugs. Cell 77,491 -502.[CrossRef][ISI][Medline]
Schinkel, A.H. (1999) P-glycoprotein, a gatekeeper in the blood-brain barrier. Adv. Drug Deliv. Rev. 36,179 -194.[CrossRef][ISI][Medline]
Smart, C.R., Ottoman, R.E., Rochlin, D.B., Hornes, J., Silva, A.R., and Goepfert, H. (1968) Clinical experience with vincristine (NSC-67574) in tumors of the central nervous system and other malignant diseases. Cancer Chemother. Rep. Part 1 52,733 -741.
Takamiya, Y., Abe, Y., Tanaka, Y., Tsugu, A., Kazuno, M., Oshika, Y., Maruo, K., Ohnishi, Y, Sato, O., Yamazaki, H., Kijima, H., Ueyama, Y., Tamaoki, N., and Nakamura, M. (1997) Murine P-glycoprotein on stromal vessels mediates multidrug resistance in intracerebral human glioma xenografts. Br. J. Cancer 76,445 -450.[Medline]
Williams, M.E., Walker, A.N., Bracikowski, J.P., Garner, L., Wilson, K.D., and Carpenter, J.T. (1983) Ascending myeloencephalopathy due to intrathecal vincristine sulfate. A fatal chemotherapeutic error. Cancer 51,2041 -2047.[CrossRef][ISI][Medline]
This article has been cited by other articles:
|
|
 |
|
  L. L. Muldoon, C. Soussain, K. Jahnke, C. Johanson, T. Siegal, Q. R. Smith, W. A. Hall, K. Hynynen, P. D. Senter, D. M. Peereboom, et al. Chemotherapy Delivery Issues in Central Nervous System Malignancy: A Reality Check J. Clin. Oncol., June 1, 2007; 25(16): 2295 - 2305. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Stupp, M. E. Hegi, M. J. van den Bent, W. P. Mason, M. Weller, R. O. Mirimanoff, J. G. Cairncross, and on behalf of the European Organisation for Researc Changing paradigms--an update on the multidisciplinary management of malignant glioma. Oncologist, February 1, 2006; 11(2): 165 - 180. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
