Verapamil Results in Increased Blood Levels of Oncolytic Adenovirus in Treatment of Patients With Advanced Cancer

Calcium channel blockers including verapamil have been proposed to enhance release and antitumor efficacy of oncolytic adenoviruses in preclinical studies but this has not been studied in humans before. Here, we studied if verapamil leads to increased replication of oncolytic adenovirus in cancer pa...

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Bibliographic Details
Published in:Molecular therapy 2012-01, Vol.20 (1), p.221-229
Main Authors: Koski, Anniina, Raki, Mari, Nokisalmi, Petri, Liikanen, Ilkka, Kangasniemi, Lotta, Joensuu, Timo, Kanerva, Anna, Pesonen, Sari, Alemany, Ramon, Hemminki, Akseli
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Adenoviridae - immunology
Adenovirus
Adenoviruses
Adolescent
Adult
Aged
Antibodies, Neutralizing - immunology
Antibodies, Viral - immunology
Calcium Channel Blockers - adverse effects
Calcium Channel Blockers - therapeutic use
Cancer therapies
Chemotherapy
Combined Modality Therapy
Cytokines
DNA, Viral - blood
Drug Synergism
Female
Gene therapy
Genetic Therapy
Genetic Vectors - administration & dosage
Genetic Vectors - adverse effects
Humans
Inflammation Mediators - blood
Laboratories
Male
Middle Aged
Neoplasm Staging
Neoplasms - mortality
Neoplasms - pathology
Neoplasms - therapy
Oncolytic Virotherapy - adverse effects
Oncolytic Viruses - genetics
Oncolytic Viruses - immunology
Original
Patients
Survival Analysis
Treatment Outcome
Tumors
Verapamil - adverse effects
Verapamil - therapeutic use
Viral Load - drug effects
Viruses
Young Adult
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Summary:Calcium channel blockers including verapamil have been proposed to enhance release and antitumor efficacy of oncolytic adenoviruses in preclinical studies but this has not been studied in humans before. Here, we studied if verapamil leads to increased replication of oncolytic adenovirus in cancer patients, as measured by release of virions from tumor cells into the systemic circulation. The study was conducted as a matched case–control study of advanced cancer patients treated with oncolytic adenoviruses with or without verapamil. We observed that verapamil increased mean virus titers present in blood after treatment (P < 0.05). The frequency or severity of adverse events was not increased, nor were cytokine responses or neutralizing antibody levels different between groups. Signs of possible treatment-related clinical benefits were observed in both groups, but there was no significant difference in responses or survival. Thus, our data suggests that the combination of verapamil with oncolytic adenoviruses is safe and well tolerated. Moreover, verapamil treatment seems to result in higher virus titers in blood, indicating enhanced overall replication in tumors. A randomized trial is needed to confirm these findings and to study if enhanced replication results in benefits to patients.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2011.230