Successful anticancer strategies require a differential response between tumor and normal tissue (i.e., a therapeutic ratio). In fact, improving the effectiveness of a cancer therapeutic is of no clinical value in the absence of a significant increase in the differential response between tumor and normal tissue. Although radiation dose escalation with the use of intensity modulated radiation therapy has permitted the maximum tolerable dose for most locally advanced cancers, improvements in tumor control without damaging normal adjacent tissues are needed. As a means of increasing the therapeutic ratio, several new approaches are under development. Drugs targeting signal transduction pathways in cancer progression and more recently, immunotherapeutics targeting specific immune cell subsets have entered the clinic with promising early results. Radiobiological research is underway to address pressing questions as to the dose per fraction, irradiated tumor volume and time sequence of the drug administration. To exploit these exciting novel strategies, a better understanding is needed of the cellular and molecular pathways responsible for both cancer and normal tissue and organ response, including the role of radiation-induced accelerated senescence. This review will highlight the current understanding of promising biologically targeted therapies to enhance the radiation therapeutic ratio.
Aging ; Radiobiology ; Radioimmunotherapy ; Signal Transduction ; Tumor Burden

Despite the increasing use of stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS) in recent years, the biological base of these high-dose hypo-fractionated radiotherapy modalities has been elusive. Given that most human tumors contain radioresistant hypoxic tumor cells, the radiobiological principles for the conventional multiple-fractionated radiotherapy cannot account for the high efficacy of SBRT and SRS. Recent emerging evidence strongly indicates that SBRT and SRS not only directly kill tumor cells, but also destroy the tumor vascular beds, thereby deteriorating intratumor microenvironment leading to indirect tumor cell death. Furthermore, indications are that the massive release of tumor antigens from the tumor cells directly and indirectly killed by SBRT and SRS stimulate anti-tumor immunity, thereby suppressing recurrence and metastatic tumor growth. The reoxygenation, repair, repopulation, and redistribution, which are important components in the response of tumors to conventional fractionated radiotherapy, play relatively little role in SBRT and SRS. The linear-quadratic model, which accounts for only direct cell death has been suggested to overestimate the cell death by high dose per fraction irradiation. However, the model may in some clinical cases incidentally do not overestimate total cell death because high-dose irradiation causes additional cell death through indirect mechanisms. For the improvement of the efficacy of SBRT and SRS, further investigation is warranted to gain detailed insights into the mechanisms underlying the SBRT and SRS.
Antigens, Neoplasm ; Cell Death ; Humans ; Radiobiology ; Radiotherapy ; Recurrence

The link between micro- and macro-parameters for radiation interactions that take place in living biological systems is described in this paper. Meanwhile recent progress and development in microdosimetry and nanodosimetry are introduced, including the methods to measure and calculate these micro- or nano-parameters. The relationship between radiobiology and physical quantities in microdosimetry and nanodosimetry was presented. Both the current problems on their applications in radiation protection and radiotherapy and the future development direction are proposed.
Humans ; Physics ; Radiation Protection ; Radiobiology ; Radiometry

The schemes of dose fractionation play an important role in tumor radiotherapy. We used mathematical methods to describe the process of tumor cells evolution during radiotherapy, trying to find how the schemes of dose fractionation affect tumor cells. In clinical radiobiology, linear-quadratic (LQ) model is frequently used to describe radiation effects of tumor cells. We integrated LQ model with effect of oxygen, and with the phenomenon of repopulation and reoxygenation in the theory of radiation biology. While we considered the disappearing progress of doomed cells in tumor, we established the mathematical model of tumor evolution in radiotherapy. We simulated some common treatment schedules, and studied the change role of tumor cells during radiotherapy. These results can serve for the optimization of dose fractionation scheme based on tumor radiobiological characteristics.
Cell Growth Processes ; radiation effects ; Dose Fractionation ; Humans ; Models, Theoretical ; Neoplasms ; pathology ; physiopathology ; radiotherapy ; Radiobiology

PURPOSE: The radiobiology of prostate cancer favors a hypofractionated dose regimen. We report here our experience with the CyberKnife(TM), demonstrating its efficacy, safety, and feasibility as a treatment modality for non-metastatic prostate cancer. MATERIALS AND METHODS: Between October 2002 and April 2006, 20 patients with biopsy-proven prostate cancer were treated with the CyberKnife(TM). The distribution of clinical risks, as assessed by using D'Amico's definition for risk grouping, was as follows: low (4), intermediate (5), and high (11). Three patients received 32 Gy, 7 patients received 34 Gy, and 10 patients received 36 Gy. All patients received the radiation doses in 4 fractions. The rectal and bladder toxicities were graded by using the criteria set forth by the Radiation Therapy Oncology Group (RTOG). RESULTS: The mean patient age was 71.4 years (range, 52-79 years), and the mean follow-up period was 35.5 months (range, 8-74 months). There were 2 acute and 1 late grade 2 gastrointestinal toxicities, and 1 acute and 2 late grade 2 urinary toxicities. The 5-year overall survival rate was 100%, respectively. The 5-year biochemical failure-free rate of the low-risk, intermediate-risk, and high-risk patients was 100%, 100%, and 90.9%, respectively. CONCLUSIONS: CyberKnife(TM) is a safe, well-tolerated, and rather effective treatment for non-metastatic prostate cancer. We obtained a 100% 5-year biochemical failure-free rate in low-risk and intermediate-risk patients. CyberKnife(TM) is a viable option for the treatment of non-metastatic prostate cancer.
Follow-Up Studies ; Humans ; Prostate ; Prostatic Neoplasms ; Radiobiology ; Radiosurgery ; Survival Rate ; Urinary Bladder

Radiosurgery is a highly precise form of radiation therapy for the treatment of vascular lesions, certain primary or metastatic neoplasms, or functional disorders. Either intracranial or extracranial, which are inaccessible or unsuitable for surgical or other management. As the basis of radiation physics for radiosurgery, this article introduces radiation history, the method of radiation production, interaction mode of radiations with human, transfer of radiation energy to the tissue, and dose planning to generate a desirable dose distribution on the target site. Biologically, the goal of radiosurgery is to cause a precise damage only to the limited tissue within the target volume without exceeding the acceptable rate of complications. As the therapeutic ratio is a function of the volume irradiated, the total dose and dose per fraction used, and the level of acceptable risk, radiation oncologists or practitioners should consider various radiobiologic factors when using radiosurgery to obtain the maximum therapeutic ratio.
Humans ; Radiobiology ; Radiosurgery

Radiosurgery, or stereotactic radiosurgery, is a minimally invasive modality to treat a lesion with stereotactically focused ionizing radiation without surgical incision. Because there are no incision procedures, general anesthesia or transfusion is not required, and complications related to incisional procedures do not occur in radiosurgery. As a result, radiosurgery shows much low rates of complications than conventional open surgery with comparable cure rates. In the beginning, radiosurgery was applied only to a few intracranial diseases because a stereotactic frame was applied to the skull. Along with the development of technologies and accumulation of knowledge on radiosurgery such as medical imaging, computer, radiation physics, and radiobiology, indications of radiosurgery have been expanded in various ways. Nowadays, radiosurgery is accepted as an adjuvant treatment or a primary treatment option for many neurosurgical diseases and cancers. Cranial nerve schwannomas, brain meningiomas, pituitary adenoma, and other benign brain tumors are good indications for radiosurgery. Intracranial arteriovenous malformation, brain metastases from extracranial cancers, and trigeminal neuralgia are also well controlled by radiosurgery. Spinal metastases and various cancers are emerging indications for extracranial radiosurgery, which has been recently introduced. In this article, the authors summarized the basic concept, history, development, and future of radiosurgery as an introduction to radiosurgery.
Anesthesia, General ; Brain ; Brain Neoplasms ; Cranial Nerves ; Diagnostic Imaging ; Intracranial Arteriovenous Malformations ; Meningioma ; Neoplasm Metastasis ; Neurilemmoma ; Pituitary Neoplasms ; Radiation, Ionizing ; Radiobiology ; Radiosurgery ; Skull ; Trigeminal Neuralgia

Locally advanced (Stage III) non-small cell lung cancer (NSCLC) accounts for approximately one third of all cases of NSCLC. Few patients with locally advanced NSCLC present with disease amenable to curative surgical resection. Historically, these patients were treated with primary thoracic radiation therapy (RT) and had poor long term survival rates, due to both progression of local disease and development of distant metastases. Over the last two decades, the use of multidisciplinary approach has improved the outcome for patients with locally advanced NSCLC. Combined chemoradiotherapy is the most favored approach for treatment of locally advanced unresectable NSCLC. There are two basic treatment protocols for administering combined chemotherapy and radiation, sequential versus concurrent. The rationale for using chemotherapy is to eliminate subclinical metastatic disease while improving local control. Sequential use of chemotherapy followed by radiotherapy has improved median and long term survival compared to radiation therapy alone. This approach appears to decrease the risk of distant metastases, but local failure rates remain the same as radiation alone. Concurrent chemoradiotherapy has been studied extensively. The potential advantages of this approach may include sensitization of tumor cells to radiation by the administration of chemotherapy, and reduced overall treatment time compared to sequential therapy; which is known to be important for improving local control in radiation biology. This approach improves survival primarily as a result of improved local control. However, it doesn't seem to decrease the risk of distant metastases probably because concurrent chemoradiation requires dose reductions in chemotherapy due to increased risks of acute morbidity such as acute esophageal toxicity. Although multidisciplinary therapy has led to improved survival rates compared to radiation therapy alone and has become the new standard of care, the optimal therapy of locally advanced NSCLC continues to evolve. The current issues in the multidisciplinary management of locally advanced NSCLC will be reviewed in this report.
Carcinoma, Non-Small-Cell Lung* ; Chemoradiotherapy ; Clinical Protocols ; Drug Therapy ; Humans ; Neoplasm Metastasis ; Radiobiology ; Radiotherapy ; Standard of Care ; Survival Rate

When tumor cells are exposed to ionizing radiation, various and complicated molecular biological changes take place leading to cell death, mutation, and recovery from sublethal damage. It has been known that DNA is the major critical target of radiation leading to cell death. The radiation-induced DNA damage activates ATM/ATR which then lead to activation and phosphorylation of downstream molecular signals, such as p53. Phosphorylation of p53 leads to inhibition of cell cycle progression, cell death through apoptosis and repair of damaged DNA. Recent evidence clearly demonstrated that p53 is directly involved in activation of cell cycle checkpoints resulting in G1 arrest and G2 arrest. During these arrests, the damaged DNA are repaired. However, when the radiation-induced DNA damage is excessive, cells undergo apoptotic cell death. Here again, p53 is involved in activation of pro-apoptotic signals such as Bax and caspases and inactivation of anti-apoptotic signals such as Bcl-2. Proper activation or intervention of these molecular signals may enable us to enhance the radiation damage in cancer cells and improve the efficacy of radiotherapy of malignant cancer.
Apoptosis ; Caspases ; Cell Cycle ; Cell Cycle Checkpoints ; Cell Death ; DNA ; DNA Damage ; Phosphorylation ; Radiation, Ionizing ; Radiobiology ; Radiotherapy*

Lung cancer is the most common malignant tumor worldwide and its incidence continues to rise each year. Recent development of molecular biologic method has led to advances in determining the etiologic factors of lung cancer and the establishment of cell lines has provided a lot of information on the through chemosensitivity, radiation biology studies, cytogenetics, and molecular biologic studies, which permits improved treatment for lung cancer. We established a small cell lung cancer cell line, designated JePa-1, obtained from malignant pericardial effusion of small cell lung cancer patient and characterized its morphologic and molecular biologic features. the JePa-1 cell line grew relatively slowly (doubling time 45hrs) as very loosely adherent floating aggregates growing in small clumps with distinct cell outlines and intertwined cords. Also JePa-1 cell line secreted antidiuretic hormones. Electronmicroscopic examination revealed that JePa-1 cell line and xenografts contained electron dense core granules, characteristic of being of neuroendocrine origin. To investigate the tumorigenic capacity, the JePa-1 cell line was injected into SCID and nude mice. Tumors taken from xenografts were observed in 3 out of 4 of the SCID mice and 2 out of 4 of the nude mice. The histologic characteristics of the xenografts were similar to those of the cell line and the original cytologic finding of the pericardial fluid, suggesting small cell carcinoma. The results of immunohistochemical markers showed reactivity for Rb protein, c-myc, TGF-alpha, TGF-beta , EGFR, keratin, NSE, chromogranin, and EMA. The DNA ploidy and the index of the JePa-1 cells was tetraploid and 2.13, respectively. The positive rate for the Rb, c-myc and K-ras proteins of the JePa-1 cell line were 98.9%, 99.3%, and 99.7% respectively as determined by flow cytometry. Cytogenetic analysis using the G-banding technique showed 65 chromosomes with various numerical and structural abnormalities. On examination of the expression of TGF-alpha, TGF-beta , and EGFR by PCR, only the EGFR was positive Through the establishment of JePa-1 cell line, we report in this paper the characterization of a small cell lung cancer such as morphologic and immunocytochemical features, growth characteristics in culture, hormone production, expression of oncoprotein and several growth factors, tumorigenicity, chromosomal abnormalities, and DNA ploidy and index. The JePa-1 cell line will be valuable in vitro studies for the etiology, treatment and the prognostic factors in small cell lung cancer.
Animals ; Carcinoma, Small Cell ; Cell Line ; Chromosome Aberrations ; Cytogenetic Analysis ; Cytogenetics ; DNA ; Flow Cytometry ; Heterografts ; Humans ; Immunohistochemistry ; Incidence ; Intercellular Signaling Peptides and Proteins ; Lung Neoplasms ; Mice ; Mice, Nude ; Mice, SCID ; Pericardial Effusion ; Ploidies ; Polymerase Chain Reaction ; Radiobiology ; Retinoblastoma Protein ; Small Cell Lung Carcinoma* ; Tetraploidy ; Transforming Growth Factor alpha ; Transforming Growth Factor beta ; Vasopressins