Local non-viral gene delivery of apoptin delays the onset of paresis in an experimental model of intramedullary spinal cord tumor

Abstract

Objective: The objective of this study is to evaluate the safety and efficacy of a tumor-specific apoptosis-inducing gene, apoptin, as delivered by the non-viral carrier, PAM-RG4, in an animal model of spinal cord tumor. Methods: Male Sprague-Dawley rats were given a 2.5-ml intramedullary injection of C6 glioma (100 000) cells and randomized into three groups (day 0). On day 5, animals received a 7.5-ml intramedullary injection of Dulbecco's modified Eagle's medium (Group 1; n ¼ 7), PAM-RG4/control gene polyplex (Group 2; n ¼ 7), or PAM-RG4/apoptin gene polyplex (Group 3; n ¼ 8). Hindlimb functional strength was assessed every other day for the duration of the study. The spinal cords of killed animals were collected and hematoxylineosin stained. Results: Following treatment, animals that received apoptin had significantly higher mean functional hindlimb scores than those of sham control animals, showing a level of preserved hindlimb function throughout the study. In addition, Group 1 (sham control) and Group 2 (control gene) animals had median survival scores lower than those of animals receiving apoptin. Histopathological analysis showed marked retardation of tumor progression in apoptin-treated animals compared with sham controls. Conclusion: Our study suggests that apoptin is safe for use in the mammalian spinal cord as well as effective in slowing the progression of tumor growth in the spinal cord. The significant slowing of tumor progression, as manifested by the preserved hindlimb function, coupled with the reduction in tumor volume, shows local non-viral delivery of apoptin could serve as an emerging therapy for the treatment of intramedullary spinal cord tumors.

Xenografting for disease modeling of intramedullary spinal cord tumors: a systematic review

“…In conclusion and based upon comparison between all AXM for IMSCT, we are convinced that intramedullary transplantation of tumor cells into the spinal cord of immunocompromised rats is currently the most established and most suitable disease model. Numerous studies have demonstrated that surgical intervention on the spinal cord of rats is safe and feasible [16][17][18][19][20][21][22][23][24][25][26][27]. Furthermore, housing of these organisms is easy and cost effective [28].…”

“…Surgical approach to the spinal cord was always performed using a laminectomy of one or two spinal column segments. In most cases, tumor cells and not tumor tissue were injected in the mid-thoracic spinal cord, which routinely led to hind limb paresis and finally to paraplegia [15,16,19,20,[22][23][24][25][26][27][30][31][32][33]. Although cervical spinal cord might be more suitable for tumor cell transplantation regarding the increased volume of central nervous tissue, this approach was less frequently performed and routinely caused autonomic dysfunction [33,34].…”

Gene Delivery Strategies to Promote Spinal Cord Repair

“…A similar starburst cationic polymer, L-arginine-grafted polyamidoamine (PAM-RG4), has been used to successfully deliver vectors encoding genes that induce tumor cell apoptosis to spinal cord tumor. 167 …”

Viral genes as oncolytic agents for cancer therapy

“…Furthermore, this combination resulted in strong natural killer activity and LLC tumor-specific CTL responses with high levels of the Th1 cytokine IL-2 and IFN-c [204]. Apoptin is also effective against brain and spinal cord tumors [205,206]. Polyamidoamine dendrimer with an arginine surface (PAM-RG4) mediated transfer of plasmid encoding apoptin (PAM-RG4/apoptin gene polyplex) effectively inhibited tumor growth in U87MG cells induced tumor in nude mice [205] and C6 cells induced tumor growth in the spinal cord of Sprague-Dawley rats [206].…”