Estimation of the relative biological effectiveness (RBE) of the Lu-DOTA-iPSMA177 radiopharmaceutical.

Relative biological effectiveness is a radiobiological parameter relevant in radiotherapy planning and useful in evaluating the physiological impact of radiation in different tissues. Targeted radionuclide therapy allows the selective and specific deposition of higher radiation doses in a noninvasive way and without collateral effects through the administration of radiopharmaceuticals. Lu-DOTA-177(hydrazinylnicotinoyl-Lys-(Nal)-NH-CO-NH-Glu) also called Lu-iPSMA177 is a third generation radiopharmaceutical composed by a peptide that recognizes the prostate-specific membrane antigen (PSMA), a membrane protein overexpressed in several types of cancer and that mediates the radiopharmaceutical's recognition of cancer cells. The present study reports radiobiological parameters of Lu-iPSMA177 and demonstrates the superiority of targeted radiopharmaceuticals over external radiotherapy treatment options in terms of their relative biological effectiveness. The relative biological effectiveness value of 1.020±0.003 for the LINAC, estimated by fitting the linear-quadratic model equation to the resulting survival curves, was like those of 1.25±0.04,1.060±0.005and1.00±0.04 obtained by an alternative method in relation to the mean lethal doses at 90, 80 or 60 survival percent respectively. While the relative biological effectiveness values of 5.65±0.13,4.72±0.27and2.87±0.19 estimated for Lu-iPSMA177 were significantly higher than those for the LINAC. The results confirm that the biological effect produced by the deposition of a radiation absorbed dose delivered by the LINAC can be induced with a quarter of that dose using Lu-iPSMA177 due to the energy distribution, dose-rate and energy fluence.

Role of gamma radiation on functional expression of the voltage-gated potassium channel Kv10.1 and its importance in the radiobiological response.

Exposure of biological systems to a radiation absorbed dose produces early and late radiogenic responses, such as ion channel modulation, oxidative stress, cell migration enhancement, and metabolic changes that could impact the efficiency of radiotherapy. To understand how radiation modulates ion channels, we irradiated HEK cells stably expressing the human ether à-go-go potassium channel-1 with gamma photons in the dose range of 2-10 Gy (60Co, 0.2 Gy/min) and measured ionic currents generated by the channel. The importance of the Kv10.1 modulation by gamma radiation was studied using cell proliferation. Results showed that a radiation-absorbed dose of 4 Gy significantly reduced the Kv10.1-evoked currents by depolarizing pulses between -100 mV and +50 mV. Additionally, the expression of Kv10.1 positively modulates HEK293 proliferation and, certainly, prevents the effect of gamma radiation on this phenomenon. Results allow concluding that the modulation of the functional expression of the Kv10.1 channel, induced by gamma radiation, leads to the expression of a radioresistant phenotype in Kv10.1 expressing cells.

Mathematical description of the effect of HIF inhibition on the radiobiological response of LNCaP cells.

According to the National Institute of Public Health, prostate cancer (PCa) is the leading cause of cancer death in Mexican men, highly associated with aggressiveness, resistance to treatment, and metastatic spread (Bharti et al., 2019) mediated by activation of the hypoxia-inducible factor 1 (HIF-1α). The objective of the present study was to evaluate the participation of HIF-1α activation in the radiobiological response of the human prostate adenocarcinoma cell line LNCaP, describing the phenomena with a mathematical model. Four groups were formed under different exposure conditions, including hypoxic cells treated with CoCl2 (300 µM for 22 h) with or without hypoxia-inducible factor inhibitor (150 nM chetomin for 4 h added after an incubation period of 18 h with CoCl2, just before completing the incubation period of 22 h). They were exposed to a source of 60Co in a dose range between 2 and 10 Gy to obtain survival curves that are fitted to a mathematical model. CoCl2 or chetomin treatments do not affect the viability of LNCaP cells that remained unchanged after irradiation. CoCl2 induced hypoxia reduces the survivability of LNCaP, and obstruction of HIF-1α signaling with chetomine produces a slight radioprotective effect. As others report, the genetic reprogramming induced by HIF-1α activation acts as an intrinsic agent that selects cells with more aggressive behavior (Pressley et al., 2017), while chetomin protects cells from death due to its scavenger properties. Interestingly, treatment with chetomin of cells induced to hypoxia (HIF-1 activation with CoCl2) produces a significant reduction in the radioresistance of LNCaP cells, demonstrating that the simultaneous use of chetomin and gamma radiation is an effective option for the treatment of hypoxic prostate cancer. At the molecular level, we suggest that the selective force exerted by HIF-1α depends on the production of free radicals by radiation. The proposed mathematical model showed that the rate of change in cell survival as a function of radiation dose is proportional to the product of two functions, one that describes cell death and the other that describes natural or artificial resistance to radiation.

Estimation of the effectiveness ratio (α/ß) for resistant cancer cells in U87MG human glioblastoma.

Glioblastoma contains self-renewing, tumorigenic cancer stem-like cells that contribute to tumor initiation and therapeutic resistance. The aim of this research was to estimate and compare the effectiveness ratio (α/ß) of stem-like cells and differentiated glioma cells derived from the U87MG glioblastoma cell line. Cell survival experiments were obtained in a dose range of 0-20 Gy (13.52 ± 0.09 Gy/h) as a hyperfractionationated accelerated radiotherapy scheme. Biochemical characterization of the post-irradiated cells was performed by flow cytometry analysis and the percentage of stem-like cells that resisted irradiation was determined by the CD133 expression. Results showed that U87MG stem-like cells are highly proliferative and more radioresistant than the U87MG adherent group (with a lesser stem-like character), this in association with the calculated α/ß ratio of 17 and 14.1, respectively.