LBL~11861 Preprintc MAY 17 LIBRARY AND To be published as a chapter in ADVANCES IN RADIATION BIOLOGY, Spring/Summer 1983, J.T. Lett, ed., Academic Press, New York, NY HEAVY-ION RADIOBIOLOGY: CELLULAR STUDIES Eleanor A. Blakely, Frank Q.H. Ngo, Stanley B. Curtis, and Cornelius A. Tobias February 1983 This a Library Circulating Copy which may be two weeks. a personal Division)' Prepared for the U.S. Department of Energy under Contract DE-AC03-76SF00098

/pdf/heavy-ion-radiobiology-cellular-studies-47x7itexvh.pdf

Heavy-Ion Radiobiology: Cellular Studies

Neon ion radiotherapy possesses biologic and physical advantages over megavoltage X rays. Biologically, the neon beam reduces the oxygen enhancement ratio and increases relative biological effectiveness. Cells irradiated by neon ions show less variation in cell-cycle related radiosensitivity and decreased repair of radiation injury. The physical behavior of heavy charged particles allows precise delivery of high radiation doses to tumors while minimizing irradiation of normal tissues. In 1979 a Phase I-II clinical trial was started at Lawrence Berkeley Laboratory using neon ions to irradiate patients for whom conventional treatment modalities were ineffective. By the end of 1988 a total of 239 patients had received a minimum neon physical dose of 1000 cGy (median follow-up for survivors 32 months). Compared with historical results, the 5-year actuarial disease-specific survival (DSS5) and local control (LC5) rates suggest that neon treatment improves outcome for several types of tumors: a) advanced or recurrent macroscopic salivary gland carcinomas (DSS5 59%; LC5 61%); b) paranasal sinus tumors (DSS5 69%; LC5 69% for macroscopic disease); c) advanced soft tissue sarcomas (DSS5 56%, LC5 56% for macroscopic disease); d) macroscopic sarcomas of bone (DSS5 45%; LC5 59%); e) locally advanced prostate carcinomas (DSS5 90%; LC5 75%); and f) biliary tract carcinomas (DSS5 28%; LC5 44%). Treatment of malignant gliomas, pancreatic, gastric, esophageal, lung, and advanced or recurrent head and neck cancer has been less successful; results for these tumors appear no better than those achieved with conventional x-ray therapy. These findings suggest that Phase III trials using the neon beam should be implemented for selected malignancies.

Neon ion radiotherapy: Results of the phase I/II clinical trial

survival curves for different temperature treatments. An Arrhenius plot of 1/To vs 1/K showed a break at 43.00C with an activation energy of 509 kcal/mole for temperatures below and 109 kcal/mole for temperatures above 43.00, respectively. Shoulder width was maximal at 42.50C with Tq equal to 126 min and n equal to about 90. Cells remained attached to the growing surface of the tissue culture flask throughout the time necessary to establish survival curves based on colony-forming ability. However, for exposure times resulting in less than 1% survival, cells detached from the flask and floated into the supernatant medium. The rate of cell detachment corresponded to the cells' loss of ability to exclude the trypan blue exclusion dye. Combining graded doses of ionizing radiation with 1-hr hyperthermic treatments at 41.5-43.00C generally resulted in small changes in the Do of the radiation survival curve, but the D, varied significantly with temperature. A synergism factor was defined as the quotient of the percentage survival expected in the event the two modalities interacted additively divided by the percentage survival actually observed from combined treatment. The synergism factor exhibited a maximum at 42.50C indicating that this may be a critical biological temperature.

https://www.jstor.org/stable/pdfplus/3575046.pdf

Response of 9L Tumor Cells to Hyperthermia and X Irradiation

Cell survival was measured for rat rhabdomyosarcoma R1 tumors irradiated in the distal 4-cm peak region of 400 MeV/u carbon- and neon-ion beams. An in vitro assay for clonogenic capacity was used to determine the surviing fraction of cells following in vivo tumor irradiation. Based on the response to 225-kV x rays under air-breathing and hypoxic conditions, it was estimated that the chronically hypoxic fraction of cells is 35%. From survival curves for tumors irradiated in air-breathing rats, RBE/sub 0/ /sub 1/ values determined at the 10% survival level were 2.0 and 3.1 for the peak carbon- and neon-ion radiation, respectively. Under hypoxic conditions, RBE/sub 0/ /sub 1/ values for peak carbon and neon ions were, respectively, 2.0 and 3.3 A diminshed oxygen effect was observed for the neon-ion relative to the carbon-ion radiation. Values of RBE for the two heavy charged-particle beams were also determined from measurements of tumor regression and regrowth following irradiation. Based on the ratio of x-ray to charged-particle doses required to produe a growth delay of 50 days, RBE/sub 50/ values for peak carbon and neon ions were 2.3 and 2.9, respectively. These RBE values are similar to those obtained in the cell survival studiesmore » and, to the extent that they reflect a large population of hypoxic cells, indicate that peak neon ions have a greater therapeutic potential than peak carbon ions for the treatment of radioresistant hypoxic tumors.« less

In vivo cell survival and volume response characteristics of rat rhabdomyosarcoma tumors irradiated in the extended peak region of carbon- and neon-ion beams.

The modification of the X ray survival response of two mammary adenocarcinoma tumor cell sublines by the polar solvent N,N-dimethylformamide (DMF) has been studied. The sublines (termed lines 66 and 67) differ significantly in their single dose survival responses to x-irradiation. Survival responses were fitted to the single-hit, multi-target, and linear-quadratic equations. For non-DMF treated cells, line 67 radiation parameters were: D 0 ( Gy ) = 1.41, D q ( Gy ) = 1.41, n (extrapolation number) = 2.73, α (10 −1 Gy −1 ) = 2.83, and β (10 −2 Gy −2 ) = 4.17. For line 66, these values were D 0 = 1.63, D g = 3.01, n = 6.4, α = 0.45, and β = 4.28. For investigation of DMF effects, cells were seeded at 1 x 10 4 per 25 cm 2 tissue culture flask in a DMF concentration of 0.8 % (0.10 M) and allowed to multiply for 4 days. For line 67, this increased the cell culture doubling time by about 27 %, and for line 66, by about 22 %. Cells were still in exponential growth at the time of irradiation. Immediately prior to irradiation, the media was removed, fresh media added and flasks were exposed to 100 kVp X rays. After exposure, cells were removed by trypsinization, counted and replated at appropriate dilution in fresh media. The survival parameters for line 67 (the radiosensitive line) then became D 0) = 1.56, D q = 0.89, n = 1.77 , α = 3.39, and β = 3.49. For line 66 (the radioresistant line), the survival parameters were D 0 = 1.56, D q , = 0.94, n = 1.83, α = 4.14, and β = 2.41. These results indicate that DMF may have the potential for modifying the low dose “shoulder” region of survival, particularly for cell lines that possess large shoulders.

Selective modification of the X ray survival response of two mouse mammary adenocarcinoma sublines by N,N-dimethylformamide.

Clonogenic cell survival of in situ 9L brain tumors was measured in air-breathing rats and rats killed with nitrogen. Animals were irradiated with BEVALAC accelerated carbon ions in the plateau and spread-out Bragg peak regions of the specific ionization curve. The relative biological effectiveness (RBE) for carbon ions in the plateau was 1.2 ± 0.1 for oxic cells and 1.3 ± 0.1 for anoxic cells; in the Bragg peak the RBE was 1.6 ± 0.1 for oxic cells and 2.0 ± 0.1 for anoxic cells. The oxygen enhancement ratio (OER) in the plateau was 2.0 ± 0.1, not significantly different from the 2.1 ± 0.2 found for x rays. The OER in the Bragg peak was reduced to 1.7 ± 0.1. For cells having the same radiobiological sensitivity as in situ 9L cells, the neon ion beam may be therapeutically superior; however, this does not preclude selection of the carbon ion beam in many clinical situations.

Cellular response of a rat brain tumour to a therapeutic neon ion beam.

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Cellular response of a rat brain tumour to a therapeutic neon ion beam.