Safety and effectiveness of a new enzyme-targeting radiosensitization treatment (KORTUC II) for intratumoral injection for low-LET radioresistant tumors

Abstract

Abstract. Linear accelerator-based radiotherapy has little effect on tumors such as malignant melanoma, various types of sarcoma, and most locally-advanced neoplasms that have grown to several centimeters or more. These tumors contain many hypoxic cancer cells or large amounts of anti-oxidative enzymes, and are therefore resistant to low linear energy transfer radiation. Therefore, it was necessary to develop a new radiosensitizer to overcome these situations. We previously developed a new enzyme-targeting radiosensitization treatment named KORTUC I, which uses 3% w/v hydrogen peroxide solution-soaked gauze. We developed a new radiosensitizer for intratumoral injection (KORTUC II), comprising a combination of hydrogen peroxide and sodium hyaluronate. After providing a fully informed written consent, 52 patients with unresectable or recurrent neoplasms (53 lesions) were enrolled in the KORTUC II trial. The present study of 52 patients with unresectable or recurrent neoplasms showed that KORTUC II is safe when injected intratumorally, well tolerated, and can efficiently exert a radiation sensitizing effect. Because this radiosensitizer is safe and less expensive than other methods, and can be applied for almost every type of low-LET radioresistant neoplasm, it has potential for worldwide and immediate use. IntroductionRadiotherapy is second to surgery as a local treatment method for malignant tumors. Because it can be applied to elderly patients and also enables normal organs and tissues to be conserved, its use has spread rapidly in recent years. However, linear accelerator (Linac) generated high-energy X-rays and electron beams that are generally used for radiotherapy are low linear energy transfer (LET) forms of radiation and therefore have a relatively weak biological effect. Accordingly, linear accelerator based radiotherapy has little effect on tumors such as malignant melanoma, various types of sarcoma, and glioblastoma multiforme. Further, because locally advanced neoplasms that have grown to several centimeters or more contain many hypoxic cancer cells or large amounts of anti-oxidative enzymes, and are therefore resistant to low-LET radiation, they are not amenable to linear accelerator based radiotherapy.Heavy particle beam therapy is a method used to improve the radiotherapeutic effect in these situations. However, the widespread use of this therapy is hampered by the cost of the equipment, which involves an investment of several tens of billions of yen.In the past 40 years, various radiosensitizers (such as metronidazole, misonidazole, etanidazole, and nimorazole) have been developed to increase the radiotherapeutic effect (1-3). However, these agents have not yet been approved for clinical practice because their effects are uncertain and they have side effects such as peripheral neuropathy.When pre-treating cancer tissue for immunohistochemical staining, peroxidase blockade is usually an essential step to avoid non-specific staining of the tissue. Most cancer tissues contain abundant peroxidase/catal...

Therapeutic results of a novel enzyme-targeting radiosensitization treatment, Kochi oxydol-radiation therapy for unresectable carcinomas II, in patients with stage I primary breast cancer

“…The majority of cancer types contain numerous hypoxic cells and/or large quantities of antioxidative enzymes, leading to radiotherapy resistance (16–26). KORTUC II exerts a marked therapeutic effect on these types of cancer.…”

“…For these forms of cancer, patients may recover completely with multidisciplinary therapy (12–15). However, the majority of cancer types contain numerous hypoxic cells and/or large amounts of antioxidative enzymes and are, therefore, resistant to radiotherapy (16–26). For these types of cancer, the novel radiosensitizer Kochi oxydol-radiation therapy for unresectable carcinomas (KORTUC) II has been developed, the concept of which is presented in Fig.…”

“…1 (18–20). Through the use of KORTUC II, hypoxic and radioresistant cancer cells become hyperoxic and radiosensitive, with demonstrable therapeutic effects (16–26). In our previous studies, the effectiveness of KORTUC II for the treatment of supraclavicular lymph node metastases, recurrent breast cancer and stage IV primary breast cancer was demonstrated (18–20).…”

Reducing Tumour Hypoxia via Oral Administration of Oxygen Nanobubbles

“…hyperbaric oxygen therapy [7], pure oxygen or carbogen breathing, ozone therapy [8], hydrogen peroxide injections [9] and administration of suspensions of oxygen carrier liquids [10]. To date, however, these approaches have delivered limited success owing to lack of proven efficacy and/or unwanted side effects [11].…”

Safety and efficacy of image-guided enzyme-targeting radiosensitization and intraoperative radiotherapy for locally advanced unresectable pancreatic cancer

“…KORTUC-III was approved for patients with advanced hepatocellular carcinoma. The efficacy of radiotherapy using KORTUC-I and −II has been demonstrated in previous clinical trials (5–8). …”