In these studies, we investigate how oxidants may affect tumor progression, focusing on whether oxidants modulate tumor cell elimination by anti-neoplastic drugs and tumor-associated macrophages. Most chemotherapeutic agents kill tumor cells by inducing apoptosis. Solid tumors are often infiltrated by inflammatory phagocytes which can generate oxidative stress within the tumor tissue. Previously, we found that in the presence of H2O2, human B lymphoma cells are unable to undergo apoptosis and die instead by a form of necrosis. We have since discovered that H2O2 inhibits induction of apoptosis by a variety of chemotherapy drugs. Most of the cells still die, but they do so more slowly, and some of the cells escape cell death altogether. The effects of H2O2 can be overcome by including antioxidants in the experimental protocol. One of the most important consequences of the interaction between H2O2 and the chemotherapy drugs is that the cells do not become phagocytosed by co-cultured macrophages until after their membranes have lysed. These findings demonstrate, for the first time, that oxidants derived from immune cells within a tumor can interfere with cancer chemotherapy by several mechanisms: (1) they decrease the degree of cell death induced by the chemotherapeutic drugs; (2) they convert the predominant form of cell death from apoptosis to necrosis; and (3) they delay phagocytosis of the dying cells by neighboring macrophages until after they have lysed and released some of their contents into the extracellular milieu. This can lead to an undesirable inflammatory reaction which can further complicate tumor cell depletion. We also demonstrated that the efficacy of chemotherapy might be improved by including anti-oxidants in the treatment protocol. This hypothesis is currently being investigated with an animal model. Studies are ongoing to elucidate the mechanism of action of H2O2. We have determined that the oxidant does not act by directly inactivating the caspase enzymes that are required for the apoptotic process. Rather, they inhibit activation of caspases upstream in the apoptotic cascade.
