First clinical experience using a ‘pathotropic’ injectable retroviral vector (Rexin-G) as intervention for stage IV pancreatic cancer

Critical Stages in the Development of the First Targeted, Injectable Molecular-Genetic Medicine for Cancer

“…With federal allowances for such commendable international collaboration in place, Rexin-G was first deployed in the clinic in the Philippines in 2002, with the tacit acknowledgement that Epeius Biotechnologies would advance its clinical development program in the USA "as soon as practicable" (U.S. FDA Communications, 2002). These pioneering clinical studies of Rexin-G in chemotherapy-resistant pancreatic cancer (Gordon et al, 2004) stand as the seminal foundations of targeted genetic medicine by (i) demonstrating the safety and single-agent anti-tumor activity of repeated intravenous infusions, (ii) affirming predicted dose-response relationships astutely extrapolated from pertinent preclinical data, and (iii) validating the tumoricidal mechanisms-of-action of Rexin-G, along with the now-classical hallmarks of tumor destruction (see Figure 7). …”

The ‘timely’ development of Rexin-G: First targeted injectable gene vector (Review)

“…As in all classical biochemical pathways, the regulatory leverage is arrayed up front, at the headwaters of the enzymatic cascades; and it is here at the mysterious boundaries of 'cell competence' which normal cells occasionally cross during the process of cell activation and cancer cells have permanently crossed in the process of neoplastic transformation that cyclin G1 is suspected to act. Induced during cell injury (54,55), activation and/or transformation (56,57), operating at the convergence of oncogenesis and tumor suppression (58)(59)(60)(61), intimately involved in the mechanisms of DNA fidelity invoked during cell cycle progression (62,63), the enforced expression of cyclin G1 advances the cell cycle (64), while its blockade is invariably lethal (13)(14)(15)(16)48,65), particularly to cancer cells, derived from all three germ layers.…”

“…The delivery of cytocidal genetic constructs that effectively destroy the target tumor cells and/or their associated blood supply eliminates the major problems associated with insertional mutagenesis and engraftment of genetically altered cells, which has plagued gene therapy applications in the past. The singular limitation of retroviral vectors that previously stymied the clinical development of these otherwise ideal gene delivery vehicles was the inability to effectively target these stealth nanoparticles under physiological conditions (22)(23)(24), a precondition that remained daunting until the advent of pathotropic targeting (11)(12)(13)(14)(15)(16)(17)(18)(19) (also see section 4).…”

“…The review assumes a posture of the medical avant-garde, but does not assume that the reader is either a molecular, genetic, or biotechnological cognoscente. The subject matter addressed herein is necessarily focused on very recent developments in the field, while pertinent background material on applied nanotechnology (2,3), gene delivery vehicles (4)(5)(6), cell cycle control (7,8), virotherapy (9,10) and tumor targeting technologies (11)(12)(13)(14)(15), as well as early clinical trials of Rexin-G (16)(17)(18) and associated histopathology (19) are available in the existing literature. The text is divided into discrete subsections in which critical distinctions are made and considered opinions are presented, in a strategic flow of contextual information that travels from the theoretical to the clinical to the analytical and beyond, to the evolving praxis of modern medicine.…”

Both HIV- and EIAV-based lentiviral vectors mediate gene delivery to pancreatic cancer cells and human pancreatic primary patient xenografts

“…16 However, low viral titers and an inability to deliver genes to nonactively growing cells present significant limitations. Lentivectors, on the other hand, can be produced to relatively high titers and can transduce both dividing and nondividing cells, optimizing the possibility for maximum transduction within the tumor.…”