INACTIVATION OF HUMAN-KIDNEY CELLS BY HIGH-ENERGY MONOENERGETIC HEAVY-ION BEAMS

Accelerated heavy particles are candidates for use in cancer therapy. The primary purpose of this investigation was to study the dose-effect relationships for asynchronous human kidney T-1 cells at various values of residual range for monoenergetic beams of carbon (400 MeV/amu), neon (425 MeV/amu), and argon (570 MeV/amu). The 'track segment' method of exposure was used to minimize variations in the distribution of energy transfer events; secondary fragments produced by the particles in their passage through matter were, however, unavoidably included. Cell survival was measured after exposure to charged-particle beams under aerobic and hypoxic conditions over a range of mean LET∞ from 10 to 600 keV/μm. Survival curves were characterized by an exponential and a nonlinear component. Using three current models for cellular inactivation, including the linear-quadratic model, the authors found that the linear inactivation coefficient increased dramatically with increasing particle charge and decreasing particle velocity. The quadratic coefficient was also found to be dependent on LET. Dose and mean LET∞ by themselves were not sufficient to characterize cellular responses. Three variables are needed: fluence, particle velocity, and particle charge; three equivalent quantities, such as dose, mean LET∞ and particle charge, may also be used. An analysis was made for the dependence of the inactivation cross section of the exponential survival term on the velocity parameter β. In an aerobic environment, the cross section varied as Z4/β4. In a hypoxic environment this cross section varied as Z4/β4.6. The total energy transfer is a function of Z2/β2 (neglecting a slowly varying logarithmic term). The radial distribution of transferred energy is a function of β2 only, and is independent of Z. Therefore, the β4.6 dependence is an indication of the importance of radial track structure. The aerobic relative biological effectiveness (RBE) values measured at 10% survival (±95% C.I.) ranged from 1.1 ± 0.2 to 2.6 ± 0.4 for the carbon beam, 1.5 ± 0.2 to 2.9 ± 0.3 for the neon beam, and 2.1 ± 0.4 to 2.7 ± 0.3 for the argon beam. Hypoxic RBE values were greater than the aerobic RBEs for all of the beams, especially at low doses, where survival is greater than 10%. The maximum aerobic and hypoxic RBEs were obtained for the neon beam at an LET of approximately 140 keV/μm. The increase in RBE with LET appears to be independent of particle charge up to about 100 keV/μm; however, above 100 keV/μm, neon and argon RBE curves separate for the same mean LET∞. The separation of the curves beyond 100 keV/μm may be a result of either the velocity dependence of the cell-killing effect and/or due to the presence of greater fragmentation contributions in the argon beam. The oxygen enhancement ratio (OER) at 10% survival drops from 2.9 ± 0.3 at low LET to a limiting 1.2 ± 0.1 in the Bragg peak of the neon and argon beams. The lowest OER measured for carbon was 1.6 ± 0.5. For the argon beam the OER was lower than 2.0 for the last 5 cm of range and lower than 1.5 for the last 2 cm of range. Although normal and tumor cells are known to have a range of biological properties, the RBE and OER results (and the LET, velocity, and charge dependence of these effects) presented here are basic to a fundamental understanding of the biological effects of charged particles. In addition, the data are relevant in future therapeutic uses of heavy ions.