Christin Glowa

Carbon ion irradiation of the rat spinal cord: Dependence of the relative biological effectiveness on linear energy transfer

PURPOSE To measure the relative biological effectiveness (RBE) of carbon ions in the rat spinal cord as a function of linear energy transfer (LET). METHODS AND MATERIALS As an extension of a previous study, the cervical spinal cord of rats was irradiated with single doses of carbon ions at 6 positions of a 6-cm spread-out Bragg peak (16-99 keV/μm). The TD50 values (dose at 50% complication probability) were determined according to dose-response curves for the development of paresis grade 2 within an observation time of 300 days. The RBEs were calculated using TD50 for photons of our previous study. RESULTS Minimum latency time was found to be dose-dependent, but not significantly LET-dependent. The TD50 values for the onset of paresis grade 2 within 300 days were 19.5 ± 0.4 Gy (16 keV/μm), 18.4 ± 0.4 Gy (21 keV/μm), 17.7 ± 0.3 Gy (36 keV/μm), 16.1 ± 1.2 Gy (45 keV/μm), 14.6 ± 0.5 Gy (66 keV/μm), and 14.8 ± 0.5 Gy (99 keV/μm). The corresponding RBEs increased from 1.26 ± 0.05 (16 keV/μm) up to 1.68 ± 0.08 at 66 keV/μm. Unexpectedly, the RBE at 99 keV/μm was comparable to that at 66 keV/μm. CONCLUSIONS The data suggest a linear relation between RBE and LET at high doses for late effects in the spinal cord. Together with additional data from ongoing fractionated irradiation experiments, these data will provide an extended database to systematically benchmark RBE models for further improvements of carbon ion treatment planning.

Split dose carbon ion irradiation of the rat spinal cord: Dependence of the relative biological effectiveness on dose and linear energy transfer

PURPOSE To measure the relative biological effectiveness (RBE) of carbon ions relative to 15 MeV photons in the rat spinal cord for different linear energy transfers (LET) to validate model calculations. METHODS AND MATERIALS The cervical spinal cord of rats was irradiated with 2 fractions of carbon ions at six positions of a 6 cm spread-out Bragg-peak (SOBP, 16-99 keV/μm). TD50-values (dose at 50% complication probability) were determined from dose-response curves for the endpoint radiation induced myelopathy (paresis grade II) within 300 days after irradiation. Using previously published TD50-values for photons (Karger et al., 2006; Debus et al., 2003), RBE-values were determined and compared with predictions of two versions of the local effect model (LEM I and IV). RESULTS TD50-values for paresis grade II were 26.7 ± 0.4 Gy (16 keV/μm), 24.0 ± 0.3 Gy (21 keV/μm), 22.5 ± 0.3 Gy (36 keV/μm), 20.1 ± 1.2 Gy (45 keV/μm), 17.7 ± 0.3 Gy (66 keV/μm), and 14.9 ± 0.3 Gy (99 keV/μm). RBE-values increased from 1.28 ± 0.03 (16 keV/μm) up to 2.30 ± 0.06 at 99 keV/μm. At the applied high fractional doses, LEM I fits best at 16 keV/μm and deviates progressively toward higher LETs while LEM IV agrees best at 99 keV/μm and shows increasing deviations, especially below 66 keV/μm. CONCLUSIONS The measured data improve the knowledge on the accuracy of RBE-calculations for carbon ions.

Carbon ion radiotherapy decreases the impact of tumor heterogeneity on radiation response in experimental prostate tumors

OBJECTIVE To quantitatively study the impact of intrinsic tumor characteristics and microenvironmental factors on local tumor control after irradiation with carbon ((12)C-) ions and photons in an experimental prostate tumor model. MATERIAL AND METHODS Three sublines of a syngeneic rat prostate tumor (R3327) differing in grading (highly (-H) moderately (-HI) or anaplastic (-AT1)) were irradiated with increasing single doses of either (12)C-ions or 6 MV photons in Copenhagen rats. Primary endpoint was local tumor control within 300 days. The relative biological effectiveness (RBE) of (12)C-ions was calculated from the dose at 50% tumor control probability (TCD50) of photons and (12)C-ions and was correlated with histological, physiological and genetic tumor parameters. RESULTS Experimental findings demonstrated that (i) TCD50-values between the three tumor sublines differed less for (12)C-ions (23.6-32.9 Gy) than for photons (38.2-75.7 Gy), (ii) the slope of the dose-response curve for each tumor line was steeper for (12)C-ions than for photons, and (iii) the RBE increased with tumor grading from 1.62 ± 0.11 (H) to 2.08 ± 0.13 (HI) to 2.30 ± 0.08 (AT1). CONCLUSION The response to (12)C-ions is less dependent on resistance factors as well as on heterogeneity between and within tumor sublines as compared to photons. A clear correlation between decreasing differentiation status and increasing RBE was found. (12)C-ions may therefore be a therapeutic option especially in patients with undifferentiated prostate tumors, expressing high resistance against photons.

Cisplatin radiosensitizes radioresistant human mesenchymal stem cells

Cisplatin-based chemo-radiotherapy is widely used to treat cancers with often severe therapy-associated late toxicities. While mesenchymal stem cells (MSCs) were shown to aid regeneration of cisplatin- or radiation-induced tissue lesions, the effect of the combined treatment on the stem cells remains unknown. Here we demonstrate that cisplatin treatment radiosensitized human bone marrow-derived MSCs in a dose-dependent manner and increased levels of radiation-induced apoptosis. However, the defining stem cell properties of MSCs remained largely intact after cisplatin-based chemo-radiation, and stem cell motility, adhesion, surface marker expression and the characteristic differentiation potential were not significantly influenced. The increased cisplatin-mediated radiosensitivity was associated with a cell cycle shift of MSCs towards the radiosensitive G2/M phase and increased residual DNA double-strand breaks. These data demonstrate for the first time a dose-dependent radiosensitization effect of MSCs by cisplatin. Clinically, the observed increase in radiation sensitivity and subsequent loss of regenerative MSCs may contribute to the often severe late toxicities observed after cisplatin-based chemo-radiotherapy in cancer patients.

OC-0543: Carbon ion irradiation response depends less on tumor heterogeneity: RBE-comparison for 3 prostate tumor sublines

mediated metabolic tumor effects using in vivo achievable biguanide concentrations. Materials and Methods: Initially we developed C labeled MET, which allowed assessment of in vitro cellular drug uptake and, importantly, in vivo biodistribution assessment using PET scans or organ dissection in tumor-bearing mice. Based on those results cellular effects of physiologically relevant doses of biguanides were tested in 14 cell lines using assays of proliferation/viability, glucose metabolism (FDG retention), respiration and lactic acid production (extracellular flux analyzer) and stress signaling. Finally, the two tumor models SiHa (cervix) and A549 (lung) were established in mice to assess acute and long-term metabolic, microenvironmental and anti-proliferative effects of PHEN treatment. Results: In vivo results showed that [MET] in blood peaked at 250 μM in mice administered maximum tolerable dose (250 mg/kg). Furthermore, MET was retained by tumor cells in vitro as well as in vivo, and uptake could be blocked by unlabeled MET suggesting involvement of OCTs. MET uptake varied widely among cell lines, with the highest uptake in A549. Likewise, inhibition of respiration and stimulation of glucose use and cell viability/proliferation was mostly affected in cell lines with high MET uptake. Even so, most cell lines were insensitive to in vivo achievable MET concentrations. PHEN was 100 times more potent than MET and induced profound metabolic changes at 50 μM in all cell lines, and down to a physiological relevant concentration of 1 μM in A549. In accordance, PHEN was chosen for further testing in tumor-bearing mice. Data analysis of tumor microenvironment (hypoxia) and growth is ongoing. Conclusions: Biguanides affect cellular energy metabolism and proliferation in vitro but metabolic effects of MET were typically restricted to non-physiological concentrations and MET retention and sensitivity varied significantly among cell lines. PHEN exerted similar effects as MET but with greater potency and may affect a broader selection of tumors at physiologically achievable concentrations. Labeling of biguanides may allow PET-based identification of patients with treatment-responsive tumors.