Summary
The development of effective chemotherapy for tumors of the central nervous system (CNS) is complicated in that the blood-brain barrier (BBB) hampers the penetration of most drugs into the brain and cerebrospinal fluid (CSF). This review summarizes the main reports on the distribution to CNS tumors and peritumoral normal brain of antitumor agents such as epipodophyllotoxins,cis-diamminedichloroplatinum(II), some nitrosoureas, bleomycin, vinblastine, and other clinically used antitumor agents as well as that of some experimental compounds with specific physicochemical properties. Drug levels were measured at surgical resection or in autopsy samples taken from patients who presented with different primary brain tumors or with brain metastases from extracerebral tumors. The observations made in each study were summarized in some detail, and the main points were then evaluated comparatively so as to highlight common aspects in the pharmacokinetic patterns of antitumor agents in human CNS tumors. Independently of their physicochemical properties, most antitumor agents appear to accumulate to a greater extent and to persist longer in intracerebral tumors than in the normal peritumoral brain. From in vitro cytotoxicity assays, it appears that epipodophyllotoxins, platinum compounds, bleomycin, and nitrosoureas reach potentially active therapeutic concentrations at the tumor target. However, all drugs have difficulty in reaching brain tissue adjacent to the tumor, as the intact BBB hampers their penetration. Plasma and CSF drug concentrations usually give little useful indication of the absolute quantity of drugs in brain tumors. To obtain a clear understanding of the CNS distribution of antitumor agents, one must determine whether the compound being measured is actually responsible for the observed activity and must consider the role of metabolites in the effect of the parent drug.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Abbreviations
- AZQ:
-
aziridinylbenzoquinone
- BBB:
-
blood-brain barrier
- CNS:
-
central nervous system
- CSF:
-
cerebrospinal fluid
- BCNU:
-
carmustine
- BLEO:
-
bleomycin
- CDDP:
-
cisplatin
- DAU:
-
3-deazauridine
- DBD:
-
dibromodulcitol
- DTIC:
-
dimethyl triazene imidazole carboxamide
- MGBG:
-
methylglyoxal bis(guanylhydrazone)
- MITXR:
-
mitoxantrone
- PALA:
-
N-phosphonacetyl-l-aspartate
- PMM:
-
pentamethylmelamine
- TCNU:
-
tauromustine
- VLB:
-
vinblastine
- VM-26:
-
teniposide
- VP-16:
-
etoposide
References
Balis FM, Poplack DG (1989) Central nervous system pharmacology of antileukemic drugs. Am J Pediatr Hematol Oncol 11: 74
Balis FM, Savitch JL, Bleyer WA, Reaman GH, Poplack DG (1985) Remission induction of meningeal leukemia with high-dose intravenous methotrexate. J Clin Oncol 3: 485
Blasberg RG, Groothuis DR (1986) Chemotherapy of brain tumors: physiological and pharmacokinetic considerations. Semin Oncol 13: 70
Bleyer XWA, Poplack DG (1979) Intraventricular versus intralumbar methotrexate for central-nervous-system leukemia: prolonged remission with the Ommaya reservoir. Med Pediatr Oncol 6: 207
Bogdahn U (1983) Chemosensitivity of malignant human brain tumors. Preliminary results. J Neurooncol 1: 149
Bonati M, Kanto J, Tognoni G (1982) Clinical pharmacokinetics of cerebrospinal fluid. Clin Pharmacokinet 7: 312
Bonnem EM, Litterst CL, Smith FP (1982) Platinum concentrations in human glioblastoma multiforme following the use of cisplatin. Cancer Treat Rep 66: 1661
Borsi JD, Moe PJ (1987) Systemic clearance of methotrexate in the prognosis of acute lymphoblastic leukemia in children. Cancer 60: 3020
Brooks DJ, Beaney RP, Thomas DGT (1986) The role of positron emission tomography in the study of cerebral tumors. Semin Oncol 13: 83
Chamberlain MC, Prados MD, Silver P, Levin VA (1988) A phase I/II study of 24 hour intravenous AZQ in recurrent primary brain tumors. J Neurooncol 6: 319
Chiras J, Dormont D, Fauchon F, Debussche C, Bories J (1988) Intra-arterial chemotherapy of malignant gliomas. J Neuroradiol 15: 31
Choucair AK (1990) Proposals for evaluation of toxic effects associated with treatment of gliomas: a call for action. J Natl Cancer Inst 82: 531
Collins JM, Dedrick RL (1983) Distributed model for drug delivery to CSF and brain tissue. Am J Physiol 245: R303
Collins JM, Grieshaber CK, Chabner BA(1990) Pharmacologically guided phase I clinical trials upon preclinical drug development. J Natl Cancer Inst 82: 1321
Csetényi J, Afra D, Kerpel-Fronius S, Horvath IP, Institoris L, Eckhardt S (1983) The distribution of [3H]-dibromodulcitol in the central nervous system of patients with brain tumour. Eur J Cancer Clin Oncol 19: 1389
Diksic M, Sako K, Feindel W, Kato A, Yamaoto YL, Farrokhzad S, Thompson C (1984) Pharmacokinetics of positron-labeled 1,3-bis(2-cholorethyl)nitrosourea in human brain tumors using positron emission tomography. Cancer Res 44: 3120
D'Incalci M, Sessa C, Beggiolin G, Mangioni C (1981) Cerebrospinal fluid levels of hexamethylmelamine andN-demethylated metabolites. Cancer Treat Rep 65: 350
D'Incalci M, Farina P, Sessa C, Mangioni C, Conter V, Masera G, Rocchetti M, Brambilla Pisoni M, Piazza E, Beer M, Cavalli F (1982) Pharmacokinetics of VP16-213 given by different administration methods. Cancer Chemother Pharmacol 7: 141
Dow LW, Sinkule JA, Look AT, Horvath A, Evans WE (1983) Comparative cytotoxic and cytokinetic effects of the epipodophyl-lotoxins 4′-demethylepipodophylotoxin-9-(4,6-O-2-ethylidene-β-d-glucopyranoside) and 4′-demethylepipodophyllotoxin-9-(4,6-O-2-thenylidene-β-d-glucopyranoside) and their metabolites on human leukemic lymphoblasts. Cancer Res 43: 5699
Duffner PK, Cohen ME, Parker MS (1988) Prospective intellectual testing in children with brain tumors. Ann Neurol23: 575
Evans WE, Sinkule JA, Crom WR, Dow L, Look AT, Rivera G (1982) Pharmacokinetics of teniposide (VM26) and etoposide (VP16-213) in children with cancer. Cancer Chemother Pharmacol 7: 147
Evans WE, Crom WR, Stewart CE, Bowman WP, Chen C-H, Abromowitch M, Simone JV (1984) Methotrexate systemic clearance influences probability of relapse in children with standard-risk acute lymphocytic leukaemia. Lancet I: 359
Evans WE, Crom WR, Abromowitch M, Dodge R, Look AT, Bowman WP, George SL, Pui C-H (1986) Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect. N Engl J Med 314: 471
Front D, Israel O, Kohn S, Nir I (1984) The blood-tissue barrier of human brain tumors: correlation of scintigraphic and ultrastructural findings: concise communication. J Nucl Med 25: 461
Front D, Even-Sapir E, Iosilevsky G, Israel O, Frenkel A, Kolodny GM, Feinsod M (1987) Monitoring of [57Co]-bleomycin delivery to brain metastases and their tumors of origin. J Neurosurg 67: 506
Front D, Israel O, Iosilevsky G, Even-Sapir E, Frenkel A, Kolodny GM, Feinsod M (1988) SPECT quantitation of cobalt-57 bleomycin delivery to human brain tumors. J Nucl Med 29: 187
Geran RI, Congleton GF, Dudeck LE, Abbott BJ, Gargus JL (1974) A mouse ependymoblastoma as an experimental model for screening potential antineoplastic drugs. Cancer Chemother Rep 4: 53
Green RM, Stewart DJ, Hogenholtz H, Richard MT, Thibault M, Montpetit V (1988) Human central nervous system and plasma pharmacology of mitoxantrone. J Neurooncol 6: 75
Greig NH (1987) Optimizing drug delivery to brain tumors. Cancer Treat Rev 14: 1
Greig NH, Sweeny D (1987) Brain tumors and the blood brain barrier. In: Neuwelt E (ed) The clinical impact of the blood-brain barrier and its manipulation. Plenum, New York, p 93
Hill BT, Whelan RDH, Rupniak HT, Dennis LY, Rosholt MA (1981) A comparative assessment of the in vitro effects of drugs on cells by means of colony assays or flow microfluorimetry. Cancer Chemother Pharmacol 7: 21
Instittoris L, Dzurillay E (1973) Comparative studies on the in vivo distribution pattern of dibromodulcitol and diepoxydulcitol. Z Krebsforsch 79: 49
Iwata K, Yung WKA, Fields WS (1988) In vitro effects of ACNU, BCNU, CDDP, and bleomycin on human glioma cells. Neurol Med Chir (Tokyo) 28: 965
Kaplan RS, Wiernik PH (1982) Neurotoxicity of antineoplastic drugs. Semin Oncol 9: 103
Kimmel DW, Shapiro JR, Shapiro WR (1987) In vitro drug sensitivity testing in human gliomas. J Neurosurg 66: 161
Lennard L, Keen D, Lylleyman JS (1986) Oral 6-mercaptopurine in childhood leukemia: parent drug pharmacokinetics and active metabolite concentrations. Clin Pharmacol Ther 40:287
Levin VA (1975) A pharmacologic basis for brain tumor chemotherapy. Semin Oncol 2: 57
Levin VA, Hoffman W, Weinkam RJ (1978) Pharmacokinetics of BCNU in man: a preliminary study of 20 patients. Cancer Treat Rep 62: 1305
Lippens RJ, Winograd B (1988) Methotrexate concentration levels in the cerebrospinal fluid high-dose methotrexate infusions: an unreliable prediction. Pediatr Hematol Oncol 5: 115
Mahaley MS, Whaley RA, Blue M, Bertsch L (1986) Central neurotoxicity following intracarotid BCNU chemotherapy for malignant gliomas. J Neurooncol 3: 297
McSheehy PMJ, Griffiths JR (1989)19F MRS studies of fluoropyrimidine chemotherapy. A review. Nucl Magn Reson Biomed 2: 133
Miller KT, Wilkinson DS (1989) Pharmacokinetics of methotrexate in the cerebrospinal fluid after intracerebroventricular administration in patients with meningeal carcinomatosis and altered cerebrospinal fluid flow dynamics. Ther Drug Monit 11: 231
Neuwelt EA (1985) Therapeutic potential for blood-brain barrier modification in malignant brain tumor. Prog Exp Tumor Res 28: 51
Neuwelt E, Hill S (1986) Chemotherapy administered in conjuction with osmotic blood-brain barrier modification in patients with brain metastases. J Neurooncol 4: 195
Newlands ES, Blackledge GRP, Slack JA, Rustin GJS, Stuart NSA, Quarterman CP, Hoffman R, Stevens MFG, Brampton MH, Gibson AC (1992) Phase I trial of temozolomide. Abstract 50, Meeting of the EORTC Pharmacology and Molecular Mechanism Group, Bologna, January 9–11
O'Dwyer PJ, Alonso MT, Leyland-Jones B, Marsoni S (1984) Teniposide. A review of 12 years of experience. Cancer Treat Rep 68: 1455
O'Dwyer PJ, Leyland-Jones B, Alonso MT, Marsoni S, Wittes RE (1985) Drug therapy. Etoposide (VP-16-213): current status of an active anticancer drug. N Engl J Med 312: 692
Ommaya AK (1984) Implantable devices for chronic access and drug delivery to the central nervous system. Cancer Drug Deliv 1: 16
Packer RJ, Sutton LN, Atkins TE, Radcliffe J, Bunin GR, D'Angio G, Siegel KR, Schut L (1989) A prospective study of cognitive function in children receiving whole-brain radiotherapy and chemotherapy: 2-year results. J Neurosurg 70: 707
Poplack DG, Riccardi R (1987) Pharmacologic approaches to the treatment of central nervous system malignancy. In: Poplack DG, Massimo L, Cornaglia-Ferraris P (eds) The role of pharmacology in pediatric oncology. Martinus Nijhoff, Boston, p 137
Poplack DG, Reaman GH, Bleyer WA, Miser J, Feusner J, Wesley R, Hammond D (1984) Central nervous system (CNS) preventive therapy with high-dose methotrexate (HDMTX) in acute lymphoblastic leukemia (ALL): a preliminary report. Proc Am Soc Clin Oncol 3: 204
Qin DX, Zheng R, Tang J, Li JX, Hu YH (1990) Influence of radiation on the blood-brain barrier and optimum time of chemotherapy. Int J Radiat Oncol Biol Phys 19: 1507
Radice PA, Bunn PA Jr, Ihde DC (1979) Therapeutic trials with VP-16-213 and VM-26: active agents in small cell lung cancer, non-Hodgkin's lymphomas, and other malignancies. Cancer Treat Rep 63: 1231
Rapoport SI, Fredericks WR, Ohno K, Pettigrew KD (1980) Quantitative aspects of reversible osmotic opening of the blood-brain barrier. Am J Physiol 238: R 421
Reid JM, Pendergrass TW, Krailo MD,Hammond GD, Ames MM (1990) Plasma pharmacokinetics and cerebrospinal fluid concentrations of idarubicin and idarubicinol in pediatric leukemia patients: a Childrens Cancer Study Group report. Cancer Res 50: 6525
Roed H, Vindelov LL, Christensen IJ, Spang-Thomsen M, Hansen HH (1987) The effect of the two epipodophyllotoxin derivatives etoposide (VP-16) and teniposide (VM-26) on cell lines established from patients with small cell carcinoma of the lung. Cancer Chemother Pharmacol 19: 16
Roper PR, Drewinko B (1976) Comparison of in vitro methods to determine drug-induced cell lethality. Cancer Res 36: 2182
Rosenblum MG, Stewart DJ, Yap BS, Leavens M, Benjamin RS, Loo TL (1981) Penetration of methylglyoxal bis(guanylhydrazone) into intracerebral tumors in humans.Cancer Res 41: 459
Rosenblum ML, Wheeler KT, Wilson CB, Barker M, Knebel KD (1975) In vitro evaluation of in vivo brain tumor chemotherapy with 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Res 35: 1387
Rosenblum ML, Dougherty DA, Deen DF, Hoshino T, Wilson CB (1980) Analysis of clonogenic human brain tumour cells: preliminary results of tumour sensitivity testing with BCNU. Br J Cancer 41 [Suppl IV]: 181
Savaraj N, Lu K, Feun LG, Leavens ME, Stewart D, Burgess MA, Benjamin RS, Loo TL (1983) Intracerebral penetration and tissue distribution of 2,5-diaziridinyl-3,6-bis(carboethoxyamino)1,4-benzoquinone (AZQ, NSC-182 986). J Neurooncol 1: 15
Sessa C, Zucchetti M, Davoli E, Califano R, Cavalli F, Frustaci S, Gumbrell L, Sulkes A, Winograd B, D'Incalci M (1991) Phase I and clinical pharmacological evaluation of aphidicolin glycinate. J Natl Cancer Inst 81: 1160
Shapiro WR (1986) Therapy of adult malignant brain tumors: what have the clinical trials taught us? Semin Oncol 13: 38
Siegers HP (1990) Chemotherapy for brain metastases: recent developments and clinical considerations. Cancer Treat Rev 17: 63
Stewart DJ (1986) Phase II study of novantrone (mitoxantrone hydrochloride) in adults with grade III–IV astrocytomas. In: Walker MD, Thomas DGT (eds) Biology of brain tumor. Martinus Nijhoff, Boston, p 411
Stewart DJ, Benvenuto JA, Leavens M, Hall SW, Benjamin RS, Plunkett W, McCredie KB, Burgess MA, Loo TL (1979) Penetration of 3-deazauridine into human brain,intracerebral tumor, and cerebrospinal fluid. Cancer Res 39: 4119
Stewart DJ, Leavens M, Friedman J, Benjamin RS, Moore EC, Bodey GP, Valdivieso M, Burgess MA, Wiseman C, Loo TL (1980) Penetration ofN-(phosphonacetyl)-l-aspartate into human central nervous system and intracerebral tumor. Cancer Res 40: 3163
Stewart DJ, Leavens M, Maor M, Feun L, Luna M, Bonura J, Caprioli R, Loo TL, Benjamin RS (1982) Human central nervous system distribution ofcis-diamminedichloroplatinum and its use as a radiosensitizer in malignant brain tumors. Cancer Res 42: 2474
Stewart DJ, Benvenuto JA, Leavens M, Smith RG, Cabanillas F, Benjamin RS, Loo TL (1983) Human central nervous system pharmacology of pentamethylmelamine and its metabolites. J Neurooncol 1: 357
Stewart DJ, Lu K, Benjamin RS, Leavens ME, Luna M, Yap H-Y, Loo TL (1983) Concentrations of vinblastine in human intracerebral tumor and other tissues. J Neurooncol 1: 139
Stewart DJ, Richard MT, Hugenholtz H, Dennery JM, Belanger R, Gerin-Lajoie J, Montpetit V, Nundy D, Prior J, Hopkins HS (1984) Penetration of VP-16 (etoposide) into human intracerebral and extracerebral tumors. J Neurooncol 2: 133
Stewart DJ, Richard MT, Hugenholtz H, Dennery J, Nundy D, Prior J, Montpetit V, Hopkins HS (1984) Penetration of teniposide (VM-26) into human intracerebral tumors. J Neurooncol 2: 315
Stewart DJ, Mikhael NZ, Nair RC, Kacew S, Montpetit V, Nanji A, Maroun JA, Howard K (1988) Platinum concentrations in human autopsy tumor samples. Am J Clin Oncol 11: 152
Tirelli D, D'Incalci M, Canetta R, Tumolo S, Franchin G, Veronesi A, Galligioni E, Trovò MG, Rossi C, Grigoletto E (1984) Etoposide (VP-16-213) in malignant brain tumors: a phase II study. J Clin Oncol 2: 432
Von Hoff DD, Coltman CA Jr, Forseth B (1981) Activity of mitoxantrone in a human tumor cloning system. Cancer Res 41: 1853
Walker MD, Weiss H (1975) Chemotherapy in the treatment of malignant brain tumors. Adv Neurol 13: 149
Watts C (1987) Blood-brain barrier and drug delivery in central nervous system tumors. Ann Neurol 21: 614
Whittle IR, MacPherson JS, Miller JD, Smyth JF (1990) The disposition of TCNU (tauromustine) in human malignant glioma: pharmacokinetic studies and clinical implications. J Neurosurg 72: 721
Workman P (1985) The pharmacology of brain tumor chemotherapy. In: Bleehen NM (ed) Tumors of the brain. Springer, Berlin Heidelberg New York, p 183
Yamada K, Takahama H, Nakai O, Takanashi T, Hosoya T (1989) Intra-arterial chemotherapy of malignant glioma after osmotic blood-brain barrier disruption. Gan To Nakagu Ryoho 16: 2692
Yung W-KA, Shapiro JR, Shapiro WR (1982) Heterogeneous chemosensitivities of subpopulations of human glioma cells in culture. Cancer Res 42: 992
Yung W-KA, Harris MI, Bruner JM, Feun LG (1989) Intravenous BCNU and AZQ in patients with recurrent malignant gliomas. J Neurooncol 7: 237
Zucchetti M, Rossi C, Knerich R,Donelli MG, Butti G, Silvani V, Gaetani P, D'Incalci M (1991) Concentrations of VP16 and VM26 in human brain tumors. Ann Oncol 2: 63
Author information
Authors and Affiliations
Additional information
This work was supported by the Italian Association for Cancer Research, by the Tettamenti Foundation, and by M.U.R.S.T. (60%) and was conducted under the auspices of the PAMM group of the EORTC
Rights and permissions
About this article
Cite this article
Donelli, M.G., Zucchetti, M. & D'Incalci, M. Do anticancer agents reach the tumor target in the human brain?. Cancer Chemother. Pharmacol. 30, 251–260 (1992). https://doi.org/10.1007/BF00686291
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00686291