The p53 tumor suppressor gene plays an important role in protecting cells from developing undesirable proliferation. The mutant p53 gene or malfunctioning p53 protein found in more than 50% of cancer cells impedes DNA repair or apoptosis induction. This may be why some cancers gain resistance to chemotherapy and radiation and become more resistant after frequent cancer treatments. A non-toxic p53 gene activator would induce cancer cell apoptosis and help damaged cancer cells to recover. Therefore, the combination use of chemotherapeutics or radiation with a non-toxic p53 gene activator will be crucial in cancer therapy, damaging DNA with chemotherapeutics or radiation on the one hand and promoting apoptosis induction with p53 gene activator on the other. This strategy would be most efficient for remission induction and maintenance in cancer therapy. Antineoplastons are naturally occurring peptides and amino acid derivatives that control neoplastic growth. Antineoplaston A10 and AS2-1 are chemically identified and synthesized antineoplastons proven to inhibit cancer cell growth by arresting the cell cycle in the G1 phase and inhibiting tumor growth by reducing mitosis. These agents are thought to be good candidates for clinically easily applicable non-toxic p53 gene activators. Our cases of advanced cancer responded well to combination treatment using chemotherapeutics and irradiation with antineoplaston A10 and AS2-1 in clinical trials being conducted in Kurume University Hospital. We describe herein the clinical cases and discuss the possible mechanism of action of this combination therapy.