Gene Therapy '97 The Promise and Reality of Cancer Gene Therapy (1997)

A variety of novel strategies for treating solid tumors by al. 1995; Xu et al. 1997). Enthusiasm has continued after a phase I clinical trial where injection of lung tugene therapy have been developed in recent years. A significant limitation in many of these methods is the mors with a p53 retrovirus was nontoxic and suppressed tumor growth in six of nine patients (Roth et al. 1996). ability to transfer therapeutic genes uniformly into all tumor cells in situ. To increase cell killing within tumors However, the field of tumor-suppressor gene therapy is limited by the paucity of identified target genes known and render metastatic disease managable, new strategies will be needed to deliver therapeutic genes systemically to induce or maintain the malignant phenotype. Furthermore, in preclinical in situ studies, eradication of treated or to induce systemic antitumor responses following local therapy. Potential shortcomings of these approaches tumors is a rarity, given the difficulty in transduction of sufficient numbers of cells within a cancer to facilitate may be addressed through the positive phenomenon of a ‘‘bystander effect’’ to broaden the destructive effects a cure. A bystander effect, whereby more cells die than are transduced, has been proposed, but neither its sigof a given therapy. Bystander effects may act locally, via cell-cell contact, or systemically, through immunenificance nor a specific mechanism(s) has yet been identified (Fujiwara et al. 1994; Lesoon-Wood et al. 1995; mediated responses. This short review will explore the ability of the three most widely studied approaches to Xu et al. 1997). Mutant or absent p53 status has been associated with resistance to radiation therapy and to cancer gene therapy and will critically evaluate each one’s ability to affect local growth and metastases and apoptosis-inducing chemotherapy (Lowe et al. 1994). Indeed, the combination of p53 gene transduction with to provoke a defined bystander effect. radiation or chemotherapy has resulted in local tumor control superior to either therapy alone (Gjerset et al. Tumor-Suppressor Gene Therapy 1995; Ngyuyen et al. 1996) and is currently under invesCancer gene therapy in its purest form is the replacetigation in clinical trial. ment, with a correct copy, of a gene whose mutation Direct suppression of metastatic growth through p53 initiates or significantly alters the malignant phenotype. gene therapy has been attempted through systemic delivCell death may not be the sole goal of such treatment: ery of a liposome complex in a breast cancer model changes in growth, behavior, invasiveness, or metastatic (Lesoon-Wood et al. 1995) or via hepatic-artery infusion ability represent other important goals in cancer confor colonic liver metastases (Bookstein et al. 1996), altainment. Since p53 is the most commonly mutated gene though both approaches lack tumor targeting. A novel in human cancer and influences transcription, cell-cycle strategy to address the treatment of p53mutant metastaarrest, DNA repair, and apoptosis (Harris 1996) as well ses has been the development of an adenovirus that replias angiogenesis (Dameron et al. 1994), it has received cates only within p53 mutant cells, killing through cell the most interest as a target for cancer gene therapy. lysis (Bischoff et al. 1996). Although not truly gene therTransduction of cancer cells with p53 can significantly apy, systemic inoculation of this vector has resulted in inhibit growth and angiogenesis or can induce apoptosis significant growth suppression of a primary tumor in p53 mutant cells in several tumor models, including (Heise et al. 1997) and deserves further investigation. lung and breast (Fujiwara et al. 1994; Lesoon-Wood et