Mechanisms of chemoresistance to alkylating agents in malignant glioma

Abstract

Intrinsic or acquired chemoresistance to alkylating agents is a major cause of treatment failure in patients with malignant brain tumors. Alkylating agents, the mainstay of treatment for brain tumors, damage the DNA and induce apoptosis, but the cytotoxic activity of these agents is dependent on DNA repair pathways. For example, O6-methylguanine DNA adducts can cause double-strand breaks, but this is dependent on a functional mismatch repair pathway. Thus, tumor cell lines deficient in mismatch repair are resistant to alkylating agents. Perhaps the most important mechanism of resistance to alkylating agents is the DNA repair enzyme O6-methylguanine methyltransferase, which can eliminate the cytotoxic O6-methylguanine DNA adduct before it causes harm. Another mechanism of resistance to alkylating agents is the base excision repair (BER) pathway. Consequently, efforts are ongoing to develop effective inhibitors of BER. Poly(ADP-ribose)polymerase plays a pivotal role in BER and is an important therapeutic target. Developing effective strategies to overcome chemoresistance requires the identification of reliable preclinical models that recapitulate human disease and which can be used to facilitate drug development. This article describes the diverse mechanisms of chemoresistance operating in malignant glioma and efforts to develop reliable preclinical models and novel pharmacologic approaches to overcome resistance to alkylating agents.

Fig 1

Growth of tumor xenografts containing various percentages of O⁶-methylguanine methyltransferase-positive cells (indicated by numbers above each curve) in animals treated with 23 mg/kg bischloroethyl nitrosourea (BCNU). Adapted with permission from Phillips et al, Cancer Res 57:4817-4823, 1997 (14).

Fig 2

Methodology for generating a murine serially transplantable xenograft model. Human glioblastomas are propagated in the flank of mice and then briefly cultured in vitro before stereotactic injection into the brains of nude mice.

Fig 3

Morphology and histopathology of glioblastomas grown in the flank. Flank tumors recapitulated human tumor morphology as evidenced by the presence of (A) high cellularity and mitotic activity (arrows) and (B) necrosis (closed arrows) and vascular endothelial proliferation (open arrows).

Fig 4

Growth of intracranial tumors established from flank xenografts. A representative section of an orthotopic tumor displays a close resemblance to primary tumors regarding advanced stage of growth. The tumor revealed high cellularity (open arrow) and invasion into corpus callosum (closed arrow).

Fig 5

Pattern of ex vivo PARP inhibition observed in PBLs from patient treated with a PARP inhibitory dose of AG-014699 27.8 mg (12 mg/m²). Abbreviations: PAR, poly(ADP)-ribose; PBL, peripheral blood lymphocytes.