Therapy of Glioblastoma Multiforme Improved by the Antimutagenic Chloroquine

Eduardo Briceño, M.D., Sandra Reyes, M. Sc., Julio Sotelo, M.D.


Neurosurg Focus. 2003;14(2) 

In This Article

Abstract and Introduction

Object: Therapy of malignant tumors is frequently curtailed by the emergence of chemoresistant cell clones. Experimentally, the authors have demonstrated that chemotherapy for glioma in rats is markedly improved by the administration of the antimutagenic quinacrine. They studied the effects of chloroquine, an antimutagenic with an optimal pharmacological profile for human use, as adjuvant for the treatment of patients with glioblastoma multiforme (GBM).
Methods: In a prospective controlled randomized trial, 18 patients with GBM underwent standard treatment with surgery, chemotherapy, and radiotherapy; nine received an additional 150-mg dose of chloroquine daily starting 1 day after surgery and continued through the observation period. Nine matched patients were included as controls. Neuroimaging studies and clinical response were periodically compared. The follow-up period ranged from 24 to 50 months. Survival time was defined as the main outcome measure.
Survival was significantly longer in chloroquine-treated patients than in controls (33 ± 5 and 11 ± 2 months, respectively [p < 0.0002]). At the end of the observation period, four patients (46%) treated with chloroquine were alive, two had evidence of tumor remission after 2 years; in another two, tumor recurrence developed after 2 and 4 years of remission, respectively. No control patient survived more than 22 months after surgery.
Conclusions: Chronic administration of chloroquine greatly enhanced the response of GBM to antineoplastic treatment. Because the cytotoxicity of chloroquine on malignant cells is negligible, these favorable results appear mediated by its strong antimutagenic effect that precludes the appearance of resistant clones during radiotherapy and chemotherapy.

Glioblastoma multiforme is the most frequent primary brain tumor in adults. Despite advances in diagnostic and surgical techniques, its prognosis remains somber; survival time in patients has not increased substantially during the last few decades.[7,21] A common drawback of antineoplastic treatment is the appearance of acquired chemoresistance, even in tumors that were initially susceptible.[4,6] The development of cell resistance to chemotherapy may be due to the survival and growth of tumor cells originally resistant or to the emergence of mutant cell clones that develop a newly acquired resistance.[9,12] Cell mutations are common in malignant neoplasms, and this feature is enhanced during chemotherapy.[14,19,23]

In a previous experimental study involving cultured C6 glioma cells and C6 rat malignant glioma, we demonstrated that quinacrine, an antimalarial drug with strong antimutagenic properties, administered in adherence to a chronic schedule maintained unchanged, the initial cytotoxic effect of the antineoplastic carmustine, which led to a high rate of tumor resolution in animals and optimal carmustine-induced toxicity in cultured C6 glioma cells.[24] Because quinacrine lacks antineoplastic properties,[2] it was apparent that the optimization of carmustine treatment for experimental malignant glioma, achieved by the addition of the antimalarial quinacrine, was due to its strong antimutagenic effect.

Here, we report a trial in patients with GBM who, in addition to standard therapies, were treated with chloroquine, an antimalarial antimutagenic compound analog to quinacrine, which was selected for the clinical study because of its great chemical and pharmacological similarities to quinacrine, its good toxicological profile, its commercial accessibility, and the vast clinical experience of several decades of use for the treatment of human malaria and some autoimmune disorders.[8,10]