Intratumoral coadministration of hyaluronidase enzyme and oncolytic adenoviruses enhances virus potency in metastatic tumor models.
OBJECTIVE
Evaluate the codelivery of hyaluronidase enzyme with oncolytic adenoviruses to determine whether it improves the spread of the virus throughout tumors, thereby leading to a greater overall antitumor efficacy in tumor models.


METHODS
The optimal dose of hyaluronidase that provided best transduction efficiency and spread of a green fluorescent protein (GFP)-expressing adenovirus within tumors was combined with oncolytic viruses in tumor models to determine whether the combination treatment results in an improvement of antitumor efficacy.


RESULTS
In mice injected with the adenovirus Ad5/35GFP and an optimal dose of hyaluronidase (50 U), a significant increase in the number of GFP-expressing cells was observed when compared with animals injected with virus only (P < 0.0001). When the oncolytic adenoviruses Ad5OV or Ad5/35 OV (OV-5 or OV5T35H) were codelivered with 50 U of hyaluronidase, a significant delay in tumor progression was observed, which translated into a significant increase in the mean survival time of tumor-bearing mice compared with either of the monotherapy-treated groups (P < 0.0001). Furthermore, the mice that received the combination of Ad5/35 OV and hyaluronidase showed the best antitumor efficacy. Importantly, the combination treatment did not increase the metastatic potential of the tumors. Lastly, the increase in virus potency observed in animals injected with both enzyme and virus correlated with enhanced virus spread throughout tumors.


CONCLUSIONS
Antitumor activity and overall survival of mice bearing highly aggressive tumors are significantly improved by codelivery of oncolytic adenoviruses and hyaluronidase when compared with either of the monotherapy-treated groups, and it may prove to be a potent and novel approach to treating patients with cancer.
Cell Genesys, Inc., South San Francisco, California 94080, USA. ganeshshanti@yahoo.com
Shanthi
S
Ganesh
Melissa
M
Gonzalez-Edick
Douglas
D
Gibbons
Melinda
M
Van Roey
Karin
K
Jooss
D000256:Adenoviridae / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000008:administration & dosage* / Q000494:pharmacology*; D015552:Injections, Intralesional; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000187:drug effects* / Q000502:physiology; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000628:therapy*; D016896:Treatment Outcome; D014779:Virus Replication / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D006821:Hyaluronoglucosaminidase