Editing Therapeutic index (section)

===Cancer radiotherapy===
Radiotherapy aims to shrink tumors and kill cancer cells using high energy. The energy arises from [[x-ray]]s, [[gamma ray]]s, or [[charged particle|charged]] or heavy particles. The therapeutic ratio in radiotherapy for cancer treatment is determined by the maximum radiation dose for killing cancer cells and the minimum radiation dose causing acute or late morbidity in cells of normal tissues.<ref name="Thoms 217–222">{{cite journal | vauthors = Thoms J, Bristow RG | title = DNA repair targeting and radiotherapy: a focus on the therapeutic ratio | journal = Seminars in Radiation Oncology | volume = 20 | issue = 4 | pages = 217–22 | date = October 2010 | pmid = 20832013 | doi = 10.1016/j.semradonc.2010.06.003 }}</ref> Both of these parameters have [[sigmoid function|sigmoidal]] [[dose–response curve]]s. Thus, a favorable outcome in dose–response for tumor tissue is greater than that of normal tissue for the same dose, meaning that the treatment is effective on tumors and does not cause serious morbidity to normal tissue. Conversely, overlapping response for two tissues is highly likely to cause serious morbidity to normal tissue and ineffective treatment of tumors. The mechanism of radiation therapy is categorized as direct or indirect radiation. Both direct and indirect radiation induce [[DNA mutation]] or [[chromosomal rearrangement]] during its repair process. Direct radiation creates a DNA [[free radical]] from radiation energy deposition that damages DNA. Indirect radiation occurs from [[radiolysis]] of water, creating a free [[hydroxyl radical]], [[hydronium]] and electron. The hydroxyl radical transfers its radical to DNA. Or together with hydronium and electron, a free hydroxyl radical can damage the base region of DNA.<ref>{{cite journal | last1 = Yokoya | first1 = A. | last2 = Shikazono | first2 = N. | last3 = Fujii | first3 = K. | last4 = Urushibara | first4 = A. | last5 = Akamatsu | first5 = K. | last6 = Watanabe | first6 = R. | name-list-style = vanc | date = 2008-10-01 | title = DNA damage induced by the direct effect of radiation | journal = Radiation Physics and Chemistry | series = The International Symposium on Charged Particle and Photon Interaction with Matter – ASR 2007 | volume = 77 | issue = 10–12 | pages = 1280–85 | doi =10.1016/j.radphyschem.2008.05.021 | bibcode = 2008RaPC...77.1280Y}}</ref>
 
Cancer cells cause an imbalance of signals in the [[cell cycle]]. G1 and G2/M arrest were found to be major checkpoints by irradiating human cells. G1 arrest delays the repair mechanism before synthesis of DNA in [[S phase]] and [[mitosis]] in M phase, suggesting it is a key checkpoint for survival of cells. G2/M arrest occurs when cells need to repair after S phase but before mitotic entry. It is known that S phase is the most resistant to radiation and M phase is the most sensitive to radiation. [[p53]], a tumor suppressor protein that plays a role in G1 and G2/M arrest, enabled the understanding of the cell cycle through radiation. For example, irradiation of [[myeloid leukemia]] cells leads to an increase in p53 and a decrease in the level of DNA synthesis. Patients with [[Ataxia telangiectasia]] delays have hypersensitivity to radiation due to the delay of accumulation of p53.<ref>{{Cite web|url=http://www.cancer.gov/about-cancer/causes-prevention/genetics/ataxia-fact-sheet#q1|title=Ataxia Telangiectasia|website=National Cancer Institute|access-date=2016-04-11}}</ref> In this case, cells are able to replicate without repair of their DNA, becoming prone to incidence of cancer. Most cells are in G1 and S phase. Irradiation at G2 phase showed increased radiosensitivity and thus G1 arrest has been a focus for therapeutic treatment.
Irradiation of a tissue induces a response in both irradiated and non-irridiated cells. It was found that even cells up to 50–75 cell diameters distant from irradiated cells exhibit a [[phenotype]] of enhanced genetic instability such as micronucleation.<ref>{{cite journal | last1 = Soriani | first1 = Renata Rabelo | last2 = Satomi | first2 = Lucilia Cristina | last3 = Pinto | first3 = Terezinha de Jesus A. | name-list-style = vanc | date = 2005-07-01 | title = Effects of ionizing radiation in ginkgo and guarana | journal = Radiation Physics and Chemistry | volume = 73 | issue = 4 | pages = 239–42 | doi = 10.1016/j.radphyschem.2005.01.003}}</ref> This suggests an effect on cell-to-cell communication such as [[paracrine]] and [[juxtacrine signaling]]. Normal cells do not lose their [[DNA repair]] mechanism whereas cancer cells often lose it during radiotherapy. However, the high energy radiation can override the ability of damaged normal cells to repair, leading to additional risk of [[carcinogenesis]]. This suggests a significant risk associated with radiation therapy. Thus, it is desirable to improve the therapeutic ratio during radiotherapy. Employing IG-IMRT, protons and heavy ions are likely to minimize the dose to normal tissues by altered fractionation. Molecular targeting of the DNA repair pathway can lead to radiosensitization or radioprotection. Examples are direct and indirect inhibitors on DNA [[double-strand break]]s. Direct inhibitors target proteins ([[Poly ADP ribose polymerase|PARP family]]) and [[kinases]] (ATM, DNA-PKCs) that are involved in DNA repair. Indirect inhibitors target protein tumor cell signaling proteins such as [[Epidermal growth factor receptor|EGFR]] and [[insulin growth factor]].<ref name="Thoms 217–222"/>

The effective therapeutic index can be affected by [[Targeted drug delivery|targeting]], in which the therapeutic agent is concentrated in its desirable area of effect. For example, in [[Radiation treatment|radiation therapy]] for cancerous tumors, shaping the radiation beam precisely to the profile of a tumor in the "beam's eye view" can increase the delivered dose without increasing toxic effects, though such shaping might not change the therapeutic index. Similarly, chemotherapy or radiotherapy with infused or injected agents can be made more efficacious by attaching the agent to an oncophilic substance, as in [[peptide receptor radionuclide therapy]] for [[neuroendocrine tumors]] and in [[chemoembolization]] or radioactive microspheres therapy for liver tumors and metastases. This concentrates the agent in the targeted tissues and lowers its concentration in others, increasing efficacy and lowering toxicity.