Luis Santana-Blank1, Elizabeth Rodríguez-Santana1, Heberto Reyes1, 2, 3, Jesús A. Santana- Rodríguez 1, Karin E. Santana-Rodríguez1
2Hospital José María Vargas, Radiology Department, Caracas-Venezuela.
3Clínica Ávila, Radiology Department, Caracas-Venezuela.
Cite this article as: Santana-Blank L, Rodríguez-Santana E, Reyes H, Santana-Rodríguez J, Santana-Rodríguez K. Laser photobiomodulation: A new promising player for the multi-hallmark treatment of advanced cancer. Int J Cancer Ther Oncol 2013;1(1):01012.
Watson, co-discoverer of the double helix structure of the DNA and a major force in cancer research over the last half century, has sharply criticized the War on Cancer on the following grounds: “Although the mortality from many cancers, particularly those of hematopoietic cells, has been steadily falling, the more important statistic may be that so many epithelial cancers (carcinomas) and effectively all mesenchymal cancers (sarcomas) remain largely incurable” 1. Thus, Watson believes, that “the cancer world is not trying to cure incurable cancer. They need to concentrate on late-state disease ” 1-2.
Indeed, efforts to increase awareness and screening have aimed to reduce late-stage disease and mortality. However, data show a significant increase in early-stages without a proportional decline in later ones 3. Fortunately, most cancers do not progress to death. Still, cancer takes a heavy toll on society in terms of patient and family suffering, lost productivity and ever straining demands on public and personal finances. In this context, made worse by a “tsunami” of baby-boomers demanding more healthcare,4 laser photobiomodulation (L-PBM), alone or combined with standard agents, may prove effective at targeting advanced cancer and other complex diseases safely and, potentially, at a low cost.
A major obstacle for many cancer drugs aiming at single molecular targets to minimizing nonspecific toxicity has been that clinical response is often transitory and followed by relapse 5. In light of this, and given that the acquisition of new-generation cancer hallmarks is intricately linked and made possible by the tumor microenvironment, it has been suggested that new anticancer therapies should not aim at single molecular targets to solely kill cancer cells, but at re-establishing homeostasis-homeokinesis, a micro-environment effect which, as will be discussed below, may be induced by light. 6
L-PBM, also known as low-energy laser therapy (LLLT), refers to the use of monochromatic or quasi-monochromatic low-fluence light to induce primarily non-thermal photochemical effects. Skepticism surrounding this multidisciplinary field has been primordially rooted in a deep belief that, to affect biological systems, electromagnetic signals must ionize matter, or that too weak a signal may not be able to trigger biological effects7. Thus, a poor understanding of the physico-chemical basis of low-energy radiation and the fact that much initial research was methodologically flawed and came from behind the former Iron Wall deterred interest in the West for decades. 8
More than three hundred worldwide publications in reputed peer reviewed journals have turned this scenario. It has been demonstrated that L-PBM can stimulate or inhibit cellular function9. It has also been ascertained that signal and target characteristics determine biological outcome, which is optimal (or even positive) only within a narrow set of parameters. Nonetheless, until recently, there was great trepidation to explore L-PBM in cancer due to fear of increasing tumor cell proliferation10-11.
Notwithstanding this, in cooperation with national and foreign research centers, our group completed animal testing and embarked on a phase I clinical trial in patients with advanced and progressive neoplasias using a singular low-energy infrared pulsed laser device (IPLD) that combines high-frequency ultrasound and near-infrared (NIR) radiation. Recruited patients, who suffered from advanced solid tumors, including epithelial cancers (carcinomas) and mesenchymal cancers (sarcomas), had exhausted available treatment alternatives and had a life expectancy ≥ 12 weeks (TNM IV- UICC).
After > 10 years of follow-up, the IPLD was found to be clinically safe and to improve performance status and quality of life. Antitumor activity was found in 88.23% of patients12. Immune data from the same trial showed modulation of CD4 CD45RA+, CD25, TNF-alpha, and soluble IL-2 receptor (sIL-2R),13 in agreement with Coussens and others14. Also in accord with subsequent results by Tanaka et al., 15 the cytomorphology results of the trial showed selective activation of programmed cellular death (i.e., apoptosis, necrosis, anoikis ) in neoplastic cells, but not in peripheral tissues. Microdensitometric T2-weighted MRI data further showed increased water content in tumor heterogeneities preceding tumor-volume reduction and therapeutic anticancer effects,16 showing that changes in water-content acted as early predicator of tumor response in a manner consistent with the approach of Ross, Chenevert and others 17-18 for early tumor response determination.
Other studies show that L-PBM can trigger regenerative responses, alone or associated with stem cell therapy19. Epigenetic modulate chromatin structure, which affects gene transcription,20 and L-PBM has been shown to reduce the frequency of chromosome aberrations21. Clinical results further suggest that L-PBM can cause phenotypic changes 22 consistent with theoretical data from a nonlinear DNA model, in which chaotic behaviors generated by damping, external fields and torque in solitone dynamics induce open states of the DNA which can regulate transcription and replication23. L-PBM has also shown effectiveness in the management of radiotherapy complications, such as mucositis 24.
Structural, kinetic, and thermodynamic implications of the above findings have been documented by our group25-27. In addition, we have proposed detailed mechanisms that complement the work of numerous authors, 28-30 and which help explain and substantiate one basic premise: that external electromagnetic energy (light) supplementation can enhance and even substitute for endogenous ATP production to power and modulate physiologically reparative mechanisms which can help reestablish homeostasis-homeokynesis, even when physiologic metabolic pathways have been compromised 31.
Recently, based on studies by Pollack and others on the exclusion zone (EZ), described as a fourth phase of water,32 we hypothesized that the EZ might be targeted by L-PBM as an energy reservoir, which cells may use to fuel cellular work and trigger signaling pathways and gene expression in the presence of injury-induced redox potentials 31. Nevertheless, we stressed that experimental proof that L-PBM would express effects via the EZ in a high-order biological system had not been attained. Now, clinical and experimental results which are remarkably consistent with the current understanding of the EZ are in press33. Such evidence, and the growing substantiation and reproduction of the above results, lead us to be confident that L-PBM will have a bright future in medicine at large, and oncology in particular.
A major goal for L-PBM in cancer is to safely control programmed cellular death and differentiation, as suggested by referred studies and in accord with the need for new multiple-hallmark cancer therapies. Challenges include determining optimal treatment parameters and further documenting the underlying mechanisms for potential applications in oncology. However, and given that laser-based technologies can be significantly less expensive than most cancer drugs, we hope that L-PBM may soon help to lower treatment costs whilst raising standard of care and quality of life, particularly, for the most vulnerable, such as the elderly, the poor and those suffering currently-untreatable late stage disease.
Conflict of Interest
The authors declare that they have no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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- Santana-Blank LA, Rodríguez-Santana E, Vargas F, et al. Phase I trial of an infrared pulsed laser device in patients with advanced neoplasias. Clin Cancer Res 2002; 8: 3082-91.
- Santana-Blank LA, Castes M, Rojas ME, Vargas F, Scott-Algara D. Evaluation of serum levels of tumour necrosis factor-alpha (TNF-alpha) and soluble IL-2 receptor (sIL-2R) and CD4, CD8 and natural killer (NK) populations during infrared pulsed laser device (IPLD) treatment. Clin Exp Immunol 1992; 90: 43-8. [CrossRef]
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