Low-Dose Radiation Therapy (LDRT) against Cancer and Inflammatory or Degenerative Diseases: Three Parallel Stories with a Common Molecular Mechanism Involving the Nucleoshuttling of the ATM Protein?
Abstract
:Simple Summary
Abstract
1. Introduction
1.1. Historical Features of Low-Dose Radiotherapy
1.2. The Molecular Features of Hormesis, AR, and HRS Phenomena Explained by A Unified Model
- Hormesis: One Gy X-rays generally induce about 40 DSB and 105 to 106 ATM monomers per human non-transformed cell. Consequently, very few DSB are induced per cell at doses lower than 1/40 Gy (i.e., 25 mGy). If some spontaneous DSB are present in cells, exposure to a dose lower than 25 mGy provides some ATM monomers that may contribute to recognizing and repairing these spontaneous DSB. Hence, if these spontaneous DSB represent a risk of cancer or aging, a dose lower than 25 mGy may decrease such a risk. This phenomenon is generally observed in group I cells since the amount of ATM monomers after irradiation is significant at such low doses by comparison with group II cells, in which the flux of ATM monomers is reduced, and in group III cells, in which DSB recognition or repair are impaired [19] (Figure 1d).
- Adaptive response: In the AR scenario, a “priming” (low) dose may produce few DSB but overall a significant amount of ATM monomers that may contribute to recognizing and repairing the DSB induced by a “challenging” (high) dose, as far as the time interval between the two doses preserves the activity of the ATM monomers in the nucleus. The AR phenomenon is generally observed in group II cells since the contribution of ATM monomers provided by the priming dose is too low (due to their sequestration in the cytoplasm by the X-proteins) to recognize all the DSB induced by the priming dose. Conversely, in group I cells, all the DSB are recognized by the high flux of ATM monomers that diffuse in the nucleus [19].
- Hypersensitivity to low dose (HRS): As said above, for the priming dose, a low dose induces few DSB and few ATM monomers. In group II cells, the sequestration of ATM monomers by overexpressed X-proteins may drastically reduce the number of ATM monomers that finally diffuse in the nucleus. Consequently, in group II cells, after a single low dose (whether after the priming dose in the frame of AR scenario or after an HRS dose), the few DSB induced by the low dose may not all be recognized and repaired by the few ATM monomers available in the nucleus. The rate of unrepaired DSB after a low dose (e.g., 0.2 Gy) could produce an effect equivalent to that produced by a dose 5 to 10 times higher (e.g., 2 Gy) [20]. Again, in group I cells, such conditions are never reached since there are no ATM–X-protein complexes, and the amount of ATM monomers is always sufficient [20,23] (Figure 1e).
- A state of the art of the application of LDRT in clinical practice;
- A review of the basic mechanisms supporting the application of LDRT;
- A unified RIANS model integrating the radiobiological bases of LDRT.
2. LDRT in Oncology
2.1. Clinical Data about LDRT against Cancer
2.2. Biological Hypotheses about the Anti-Cancer Effect of LDRT
2.3. The HRS Phenomenon and the RIANS Model
3. LDRT in Inflammation-Related Pathologies
3.1. Clinical Data about LDRT against Inflammation in Rheumatology
3.2. Clinical Data about LDRT against Inflammation after COVID-19 Infection
3.3. Biological Hypotheses about the Anti-Inflammatory Effect of LDRT
3.4. Tissue Inflammation and the RIANS Model
4. LDRT in Alzheimer’s Disease (AD)
4.1. LDRT Clinical Trials in AD Patients
4.2. Biological Hypotheses about the Beneficial Effect of LDRT for AD
4.3. Degenerative Diseases and the RIANS Model
5. Conclusions
6. Patents
Author Contributions
Funding
Conflicts of Interest
References
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Target | Study Design | Irradiation Scheme | Response | Reference | |
---|---|---|---|---|---|
Haemato-oncology | |||||
68 patients with NHL (90% stage III and IV) | Whole body | Retrospective | LD-TBI: midline 0.1 Gy per session (1.78 Gy total) | Recurrence-free survival: 32% at 5 years, 27% at 10 years | [30] |
26 patients with NHL (stage III and IV) | Whole body | Prospective, non-randomized (pilot study) | Chemotherapy and 2 courses of LD-TBI: 5 × 0.15 Gy per session (separated by 2 weeks), followed 1 month later by radical involved-field RT (20 × 2 Gy per session) | Complete remission in 92.3% (24/26) of patients after LD-TBI and before IF-RT; Complete remission in 96.2% (25/26) of patients after IF-RT | [31] |
Distant metastases | |||||
8 patients with metastatic tumor nodules | Metastases | Randomized study | Standard fractionated RT: 12 × 1.5 Gy per session or ultra-fractionated RT: 0.5 Gy/4 h over 12 days | Significantly increased growth delay in nodules treated with the ultra-fractionated RT scheme | [32] |
18 patients with metastatic colorectal cancer | Metastases | Phase II | 0.2 Gy per session every 6 h interval (on each chemotherapy cycle) | Clinical or pathological complete response in 38.9% (7/18) of patients | [33] |
A 73-yr woman with metastatic vaginal mucosal melanoma progressing on immunotherapy | Metastases | Case report | LDRT: 5 × 1 Gy per session (liver metastasis); 6 × 1 Gy per session (inguinal lymph node) | Clinical and radiographic complete response | [34] |
74 patients with metastatic cancer (NSCLC, n = 38; melanoma, n = 21) progressing on immunotherapy within 6 months | Metastases | Phase II | HDRT alone: 3–12.5 Gy per session (20–70 Gy total) or HDRT + LDRT: 0.5–2 Gy per session (1–10 Gy total) | 4-month disease control response: 47% in HDRT + LDRT vs. 37% in HDRT alone (p = 0.38); Overall response: 26% in HDRT + LDRT vs. 13% in HDRT (p = 0.27) | [35] |
Target | Study Design | Irradiation Scheme | Response | Reference | |
---|---|---|---|---|---|
Rheumatology | |||||
166 patients with painful skeletal disorders (calcaneodynia, n = 51; achillodynia, n = 8; gonarthrosis, n = 80; bursitis trochanterica, n = 27) | Joints/bone | Prospective | 0.5–1 Gy per session (6 Gy total) | Good response in 37.3% (62/166) of patients immediately on completion of RT and in 49.5% (54/109) of patients after a median follow-up of 29 months (p = 0.001) | [55] |
196 patients with ankle/foot osteoarthritis | Joints | Prospective | 0.5–1 Gy per session (3–6 Gy total) over 3 weeks | Subjective improvement of 80–100% in 37% (71/196) of patients | [56] |
56 patients with knee/hand osteoarthritis | Joints | Randomised, sham-controlled | LDRT: 6 × 1 Gy per session or sham | No significant evidence of beneficial LDRT effect | [57] |
55 patients with knee osteoarthritis | Joints | Randomised, double-blinded, sham-controlled | LDRT: 6 × 1 Gy per session or sham | No significant evidence of beneficial LDRT effect | [58] |
56 patients with hand osteoarthritis | Joints | Randomised, blinded, sham-controlled | LDRT: 6 × 1 Gy per session or sham | No significant evidence of beneficial LDRT effect | [59] |
COVID-19 | |||||
36 COVID-19 patients | Bilateral whole lungs | Prospective | 1 × 0.5 Gy per session | SAFI improved from 255 mmHg to 283 mmHg at 24 h and to 381 mmHg at 1 week, respectively | [65] |
41 COVID-19 patients | Bilateral whole lungs | Prospective phase I-II | 1 × 1 Gy per session | SAFI significantly improved on day +3 and +7 (p < 0.01) | [66] |
25 COVID-19 patients | Bilateral whole lungs | Phase II | 1 × 0.5 Gy per session | SAFI significantly improved between pre-RT and day +2 (p < 0.05), +3 (p < 0.001) and +7 (p < 0.001) post-RT; oxygen supply significantly decreased between pre-RT and day +2 (p < 0.05), +3 (p < 0.001), and +7 (p < 0.001) post-RT | [67] |
30 COVID-19 patients | Bilateral whole lungs | Multicenter, prospective, observational | 1 × 0.5 Gy per session | SAFI significantly improved; oxygen supply decreased | [68] |
20 COVID-19 patients | Bilateral whole lungs | Randomized, double-blinded | 1 × 1 Gy per session or sham | No significant evidence in 15-day ventilator-free days (p = 1.00) nor overall survival at 28 days (p = 0.69) in both arms; lymphocyte counts significantly decreased after LDRT (p < 0.01) | [69] |
100 COVID-19 patients | Bilateral whole lungs | Phase II, randomized | LDRT: 1 × 0.35 Gy per session or 1 × 1 Gy per session or sham | Recruiting since 2020 | NCT04466683 (Ohio State University Comprehensive Cancer Center, Columbus, OH, USA) |
52 COVID-19 patients | Bilateral whole lungs | Phase III, randomized | 1 × 1.5 Gy per session or sham | Recruiting since 2020 | NCT04433949 (Emory University Atlanta, GA, USA) [70] |
Target | Study Design | Irradiation Scheme | Response | Reference | |
---|---|---|---|---|---|
An 81-yr-old woman with AD | Brain | Case report | 5 × 40 mGy/CT over 3 months | Clinical cognitive improvement allowing discharge from hospice care | [93] |
A 73-yr-old man with AD | Brain | Case report | 6 × 45–50 mGy/CT over 18 months | Elevation of MMSE score from 22/30 up to 26/30 | [95] |
4 AD patients | Brain | Single-arm (pilot study) | 4 × 40 mGy/CT over 1 month | Slight cognition and behavior improvements on quantitative measures (SIB, ADL) | [102] |
30 AD patients | Brain | Phase I (single-arm pilot study) | 5 × 2 Gy per session 10 × 2 Gy per session | Suspended due to staffing and budget limitations | NCT02359864 (William Beaumont Hospitals, Royal Oak, MI, USA) |
5 AD patients | Brain | Phase IIa (single-arm pilot study) | 5 × 2 Gy per session 10 × 2 Gy per session | Interrupted due to COVID-19 | NCT02769000 (Virgina Commonwealth University, Richmond, VA, USA) |
20 AD patients | Brain | Randomized, monocentric, prospective (pilot study) | 5 × 2 Gy per session | Recruiting since 2017 | NCT03352258 (Geneva University Hospital, Geneva, Switzerland) |
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Le Reun, E.; Foray, N. Low-Dose Radiation Therapy (LDRT) against Cancer and Inflammatory or Degenerative Diseases: Three Parallel Stories with a Common Molecular Mechanism Involving the Nucleoshuttling of the ATM Protein? Cancers 2023, 15, 1482. https://doi.org/10.3390/cancers15051482
Le Reun E, Foray N. Low-Dose Radiation Therapy (LDRT) against Cancer and Inflammatory or Degenerative Diseases: Three Parallel Stories with a Common Molecular Mechanism Involving the Nucleoshuttling of the ATM Protein? Cancers. 2023; 15(5):1482. https://doi.org/10.3390/cancers15051482
Chicago/Turabian StyleLe Reun, Eymeric, and Nicolas Foray. 2023. "Low-Dose Radiation Therapy (LDRT) against Cancer and Inflammatory or Degenerative Diseases: Three Parallel Stories with a Common Molecular Mechanism Involving the Nucleoshuttling of the ATM Protein?" Cancers 15, no. 5: 1482. https://doi.org/10.3390/cancers15051482
APA StyleLe Reun, E., & Foray, N. (2023). Low-Dose Radiation Therapy (LDRT) against Cancer and Inflammatory or Degenerative Diseases: Three Parallel Stories with a Common Molecular Mechanism Involving the Nucleoshuttling of the ATM Protein? Cancers, 15(5), 1482. https://doi.org/10.3390/cancers15051482