Intracerebral adenovirus-mediated p53 tumor suppressor gene therapy for experimental human glioma

Malignant gliomas of astrocytic origin are good candidates for gene therapy because they have proven incurable with conventional treatments. Although mutation or inactivation of the p53 tumor suppressor gene occurs at early s tages in gliomas and is associated with tumor progression, many tumors incl uding high-grade glioblastoma multiforme carry a functionally intact p53 ge ne. To evaluate the effectiveness of p53-based therapy in glioma cells that contain endogenous wild-type p53, a clinically relevant model of malignant human glioma was established in athymic nu/nu mice. Intracerebral, rapidly growing tumors were produced by stereotactic injection of the human U87 MG glioma cell line that had been genetically modified for tracking purposes to express the Escherichia coli lacZ gene encoding beta-galactosidase. Over expression of the p53 gene by adenovirus-mediated delivery into the tumor m ass resulted in rapid cell death with the eradication of beta-galactosidase -expressing glioma cells through apoptosis. In long-term experiments, the s urvival of mice treated with the p53 adenoviral recombinant was significant ly longer than that of mice that had received control adenoviral recombinan t. During the observation period of 1 year, a complete cure was achieved in 27% of animals after a single injection of p53 adenoviral recombinant, and 38% of the animals were tumor free in the group receiving multiple injecti ons of p53 adenoviral recombinant into a larger tumor mass. These experimen ts demonstrate that overexpression of p53 in gliomas, even in the presence of endogenous functional wildtype p53. leads to efficient elimination of tu mor cells. These results point to the potential therapeutic usefulness of t his approach for all astrocytic brain tumors.