Morphine facilitates doxorubicin penetration in the central nervous system: a new prospect for therapy of brain tumors

Abstract

Doxorubicin (DOX) is an anthracycline antibiotic produced by Streptomyces peucetius which interferes with DNA and RNA synthesis by inhibiting topoisomerase II. This drug is used in the treatment of a wide variety of tumors such as carcinomas, sarcomas, leukemias and lymphomas. Clinical trials have, however, demonstrated very limited efficacy in the treatment of brain tumors, due to inefficient accumulation in the brain parenchyma [1]. In fact, DOX is a substrate of the MDR1 isoform of P-glycoprotein (P-gp) efflux transporter that usually very efficiently removes drugs from the central nervous system (CNS) [2].In vitro studies have demonstrated that DOX displays high antitumor activity on glioblastoma cells. Moreover, in vivo data on animal models of malignant glioma suggest that DOX is an effective anti-glioma agent [3,4].Therefore, several strategies have been tested for improving anthracycline delivery to brain parenchyma through circumvention of the blood-brain barrier (BBB). Recently, intracerebral drug delivery of DOX via a polymer matrix in brain tumors of rat has been successfully performed [5]. A clinical study has shown encouraging results with intralesional DOX infusion via an Ommaya reservoir without significant systemic side effects for therapy of high grade gliomas [6].Some effort has focused on the role of bradykinin, methamphetamine and more recently of PDE5 inhibitors on BBB permeability in rodent models. It has been proposed to use these molecules for opening the BBB during administration of chemotherapy agents not normally able to effectively cross it [7][8][9][10].Morphine is the most frequently used analgesic in oncological cancer patients. Its wider use has been repeatedly advocated by scientists, patients' associations and the media in order to combat old prejudices restricting its use to cancer patients. Documented clinical experience has shown that therapeutic doses of morphine may be indicated and safely instituted in the course of a patient's illness and continued for many months. Risks of morphine at analgesic dosage, however, are low. Sharma and Ali [8] demonstrated in a rodent model that this opioid agent temporarily alters the permeability of BBB for large molecules. A modulation of the BBB by morphine could therefore act as permeability enhancer also for chemotherapy agents, as anthracyclines, normally unable to effectively enter the brain.Our group recently verified that morphine pre-treatment facilitates DOX delivery beyond the BBB to the brain in the absence of signs of increased acute systemic toxicity in a rat model. The mean concentration of DOX in the cerebral hemispheres of rodents receiving doxorubicin alone was 5.88 ± 0.34 ng/g fresh tissue versus 18.8 ± 1.01 ng/g fresh tissue in those treated with DOX plus morphine. Coadministration of morphine did not increase the levels of DOX in heart and kidney tissues. Plasma LDH activity and MDA levels, as markers of acute cardiotoxicity, were similar in rats treated with DOX alone compared to those also receiving morphine [11].Thu...

Tumor response of temozolomide in combination with morphine in a xenograft model of human glioblastoma

“…The first step experiment was then performed combining TMZ treatment (1,77 mg/kg) with morphine (10 mg/kg) [ 16 – 20 ].…”

“…Basing on literature data regarding the pharmacological modulation of BBB by morphine [ 17 ], the most commonly used opioid in oncological patients, we have recently demonstrated that this agent is able to increase delivery and efficacy of doxorubicin (Dox) in animal models, without increasing systemic toxicities [ 18 , 19 , 20 , 21 ].…”

The blood-brain barrier and methamphetamine: open sesame?

“…The observation that BBB breakdown is transient and thus resembles an agonist-driven (or therapeutic) opening of the BBB, suggests that METH and related compounds could be used to enhance the transport of other drugs to the CNS. Indeed, this is an idea proposed as early as 2007 (Kast, 2007 ) and, given that METH is FDA approved, has been picked up repeatedly since (Focosi and Kast, 2010 ; Sardi, 2011 ; Capeloa et al, 2014 ). However, preclinical or clinical data in support of such a therapeutic strategy have not yet been reported.…”

Blood-Brain Barrier and Breast Cancer Resistance Protein: A Limit to the Therapy of CNS Tumors and Neurodegenerative Diseases

“…facilitates the delivery of the anticancer agent into the brain, in absence of signs of increased acute systemic toxicity. A quantitative analysis of DOX was performed by LC-MS/MS mass spectrometry; the mean concentration of DOX in the cerebral hemispheres of rodents receiving DOX alone was 5.88±0.34 ng/g fresh tissue versus 18.8±1.01 ng/g fresh tissue in those treated with DOX plus Morph [65, 66]. Thus, it is conceivable that Morph competing with the efflux transporters localized on BBB could increase the access of DOX to the brain [67].…”