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Do anticancer agents reach the tumor target in the human brain?

  • Review
  • Antitumoral Agents, Brain Pharmacokinetics, Central Nervous System, Human Tumors
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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.

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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

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Authors and Affiliations

  1. Instituto di Ricerche Farmacologische Mario Negri, via Eritrea 62, 20 157, MILANO, Italy

    M. G. Donelli, M. Zucchetti & M. D'Incalci

  2. Dipartimento di Biologia e Genetica per le Scienze Mediche, Via Viotti 3/5, Milano, Italy

    M. G. Donelli

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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

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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

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