Investigation of the relative biological effectiveness and uniform isobiological killing effects of irradiation with a clinical carbon SOBP beam on DNA repair deficient CHO cells

Abstract

Abstract. Spread-out Bragg peak (SOBP) C ions have been used clinically in charged particle radiation therapy for years. An SOBP beam consists of various monoenergetic Bragg peaks; however, the biological effect of irradiation with an SOBP beam track has not been well-studied. In order to determine the clinically prospective molecular targets, radiosensitivity to the beam track in DNA repair deficient cell lines was investigated. A total of four distinct Chinese hamster ovary (CHO) cell lines, including CHO10B2 (wild-type), V3 (protein kinase DNA-activated catalytic polypeptide deficient), 51D1 (RAD51 paralog D deficient) and PADR9 [poly(ADP-ribose) polymerase (PARP) deficient], were irradiated with gamma-rays, C ions (290 MeV/n) and Fe ions (500 MeV/n), in order to compare cellular lethality. An OptiCell™ culture system was used to evaluate the lethality at distinct depths of SOBP C ions. Relative biological effectiveness (RBE) values of C ions (linear energy transfer (LET), 13 and 70 keV/µm) and Fe ions (LET, 200 keV/µm) were calculated from cell survival using colony formation assay with standard cell dishes. All cell lines exhibited similar sensitivity to 70 keV/µm C ions and 200 keV/ µm Fe ions. Furthermore, V3 cells did not exhibit increased sensitivity to high LET C ions and Fe ions, compared with low LET gamma-rays and C ions, and 51D1 cells irradiated with 13 keV/µm C ions exhibited relatively high RBE values among the tested cell lines. Conversely, PADR9 cells exhibited low RBE values for 13 keV/µm C ions and high RBE values for 70 keV/µm C ions. Obtained using the OptiCell system, the survival fractions in the SOBP region were uniform for wild-type and PADR9 cells. Conversely, V3 and 51D1 cells exhibited decreased cell death in the distal region of the SOBP. These results indicated that PARP is a more effective target for clinical beam therapy, compared with the non-homologous end joining repair and homologous recombination repair pathways. PARP deficiency may be an optimal target for C ion therapy and the results of the present study may contribute to the development of a more effective heavy ion radiation therapy. IntroductionHeavy ion radiation therapy began in the 1970s in the USA as a more efficient radiation therapy compared with classical X-ray therapy (1,2). Heavy ion therapy is gaining prevalence, and has been increasingly utilized in Japan, China, Germany and Italy (1,2). Heavy ions exhibit three advantageous cancer cell killing characteristics when compared with X-rays. Heavy ions exhibit a more efficient dose distribution in cancer tissues due to the Bragg peak. The phenomenon allows for the majority of the dose to be deposited within the cancer tissues, avoiding unnecessary radiation exposure to normal tissues. In addition, heavy ions form complex DNA lesions within the cell due to the large amount of energy deposited during particle/DNA interactions. Heavy ions are able to produce more complex DNA lesions compared with X-rays and gamma-rays (1,2). Complex DNA damage lesions are more diff...

Activation of Sonic Hedgehog Signaling Is Associated with Human Osteosarcoma Cells Radioresistance Characterized by Increased Proliferation, Migration, and Invasion

“…The radiosensitivity of MG63 and MG63R was assessed by colony formation assay. This assay was carried out by using OptiCell culture chambers (Thermo Scientific) according to previous descriptions [ 16 ]. Cell culture medium containing 400–600 cells at a volume of 10 ml was added to each chamber.…”

Emodin Impairs Radioresistance of Human Osteosarcoma Cells by Suppressing Sonic Hedgehog Signaling

“…The radiosensitivity of MG63 cells and MG63R cells was assessed by colony formation assay. This assay was carried out by using OptiCell culture chambers according to previous descriptions [ 14 ]. Cell culture medium containing 400–600 cells at a volume of 10 mL was added to each chamber.…”

Combination Therapy With Charged Particles and Molecular Targeting: A Promising Avenue to Overcome Radioresistance

“…When both PARP signaling and homologous recombination was inhibited, lung cancer and pancreatic cancer cells showed enhanced proton radiation-induced cell killing (171). For carbon ion irradiation, multiple in vitro studies have shown that the use of a PARP inhibitor can sensitize cancer cells to carbon ion irradiation (Table 3) (97,98,212). Interestingly, some of these studies showed that PARP inhibition has a higher radiosensitizing effect in combination with carbon ion radiation compared to photon irradiation (97,98,101).…”