![]() ![]() One of those compounds was (3,4-dihydro-2,2-dimethyl-2H-naphtholpyran-5,6-dione), also known as β-lapachone. The goal was to thwart cancer cells’ ability to repair IR damage, to avoid the survival of IR-resistant malignant cells that have undergone potentially lethal damage repair (PLDR). In the late 1980s, our laboratory began searching for DNA repair modulators that synergize with ionizing radiation to kill cancer cells more effectively. ![]() Thus, methods to improve the safety and efficacy of ionizing radiation were initiated, including combination with chemotherapeutics or radiosensitizers.ģ.1 Initial discovery of β-lapachone’s effect on DNA repair Some tumors can also be resistant to radiotherapy, including hypoxic tumors and dormant cancer cells that regrow when the optimal tumor microenvironment presents itself. Despite improvements in targeting tumors and reducing normal tissue damage, high doses of radiation are still required for a curative effect. Current approaches include conformal radiation therapy, proton beam radiation therapy, stereotactic radiation therapy (using linear accelerators or gamma knife devices), and intraoperative therapy. ![]() Today, patients benefit from vast technological improvements, allowing for focused radiation beams, which markedly increased patient survival. Initially, radiation was delivered using unfocused beams, causing skin and blood malignancies in both patients and radiologists. ![]() The late 19th-century discovery of the X-ray by Wilhelm Roentgen led to diagnostic tools and therapies for diseases such as blood disorders and benign and malignant growths. *Address all correspondence to: Initial use of ionizing radiation Translational Research Core, Simon Cancer Center, Indiana University School of Medicine, United States of America.Department of Radiation Oncology, Simon Cancer Center, Indiana University School of Medicine, United States of America.Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, United States of America.The combination treatment is effective in preclinical animal models with NSCLC, prostate, and head and neck xenografts, indicating that clinical trials are warranted. Similarly, a lower IR dose can be used in combination with the drug, reducing the effects of IR on normal tissue. Combining IR with NQO1-bioactivatable drugs allows for a reduction in drug dose. Exposure of human cancer cells overexpressing NQO1 to NQO1-bioactivatable drugs immediately following IR, therefore, hyperactivates PARP1 synergistically, which in turn depletes NAD+ and ATP, inhibiting DSB repair. These hyperactivate poly (ADP-ribose) polymerase 1 (PARP1) and dramatically increase calcium release from the endoplasm reticulum (ER). NQO1-bioactivatable drugs (e.g., β-lapachone and deoxynyboquiones) also promote abasic DNA lesions and SSBs. Ionizing radiation (IR) creates a spectrum of DNA lesions, including lethal DNA double-strand breaks (DSBs), and mutagenic but rarely lethal altered DNA bases and DNA single-strand breaks (SSBs). Non-small cell lung (NSCLC), pancreatic (PDAC), prostate, and breast cancers overexpress NQO1. We developed a novel means of radiosensitization, exploiting NAD(P)H:Quinone Oxidoreductase 1 (NQO1) overexpression, and lowered catalase expression in solid human tumors using NQO1-bioactivatable drugs. Developing cancer therapeutics that radiosensitize in a tumor-selective manner remains an ideal. ![]()
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