Sensitizers and protectors of radiation and chemotherapy

doi:10.1067/mcn.2001.120122

Current Problems in Cancer

Volume 25, Issue 6, November–December 2001, Pages 334-411

https://doi.org/10.1067/mcn.2001.120122 Get rights and content

Abstract

Curr Probl Cancer 2001;25:329-412.

Section snippets

Background

Radiation dose can be conceptualized as a prescribed dose within an isodose curve. Choosing the appropriate radiation dose for a patient depends on several factors, such as extent of disease, tumor type, normal tissue within the irradiated field, and definitive or palliative intention to treat. To plan a radiation treatment, computer models calculate the dose administered by a combination of various beam energies and beam positions. Dose, prescribed in gray (or centigray), is based on the

Considerations for modifiers

Theoretically, radiation and chemotherapy modifiers differ from traditional anticancer agents because they are not intended to be cytotoxic. A critical characteristic of modifiers is selectivity. Sensitizers should be selective for tumor whereas a protector should be selective for normal tissue. An agent without selectivity and that enhances normal tissue and tumor effect equally is probably not of value. This situation is no different than administering a higher dose of radiation or

Combined modality therapy

The concepts driving the development of radiation modifiers are similar to that of combined modality therapy with radiation and standard chemotherapeutic agents.⁸ The exception is that modifiers are generally not designed to be cytotoxic.

In the 1950s investigators began searching for chemical agents that might enhance the effects of radiation,9, 10 giving rise to concurrent chemoradiation. Heidelberger et al¹¹ in 1958 in a preclinical study obtained “potentiation of activity” by combining

Radiation sensitizer mechanisms

The mechanism by which agents sensitize cells to radiation can be divided into three main categories:

Clinical trial methodology

A discussion of the mechanisms by which agents sensitize cells to radiation would be incomplete without mention of the studies conducted to evaluate these agents. Clinical trials start with the assumption that the results and perhaps even the mechanisms observed with in vitro and in vivo laboratory models will translate into the clinical model. Few clinical studies, however, are designed to evaluate the actual operational mechanisms in the human model.³⁸ For instance, preclinical studies have

Normal tissue toxicity

Three-dimensional-conformal treatment can reduce the dose and volume of normal tissue treated with the aim of adequately treating microscopic tumor at the margin of the field. Radiation protectors such as amifostine⁴⁰ may be helpful in this regard. In fact, recent work suggests that the late effects of radiation may be partially reversible.⁴¹ Nitroxides, another new class of radioprotective agents, are currently being studied preclinically.⁴² Nitroxides exhibit selective normal tissue

Hypoxia

The most studied strategy to clinical radiosensitization has focused on targeting hypoxic tumor cells. For more than 70 years, the importance of the oxygen effect in cell killing by ionizing radiation has been known. To kill the same proportion of hypoxic cells compared with oxic cells, approximately 2 to 3 times the radiation dose is required. The oxygen enhancement ratio (OER), which is the radiation dose without oxygen divided by the radiation dose without oxygen to achieve the same end

Hypoxia summary

On the basis of surveys of rodent tumors and human tumor xenografts, almost all solid tumors contain hypoxic cells.73, 74 Studies with microelectrodes that measure oxygen content directly and autoradiography studies with agents that selectively bind to hypoxic cells have identified the presence of hypoxic cells within human tumors.68, 69 The Eppendorf oxygen electrode is the most commonly used technique to quantify hypoxia.54, 76, 77, 109, 110 Representative results (Fig 3) are showed in a

Chronic and acute nutrient deprivation and reoxygenation

The initial model of hypoxia was developed by Thomlinson and Gray,⁵¹ who noted the pathologic appearance of small necrotic foci at approximately 150 μm from the capillaries in lung cancer specimens. This “diffusion-limited” or chronic hypoxia is one type of hypoxia. The other type is “perfusion-limited” or intermittent, acute hypoxia. Figure 4 is a schematic illustration of the two types of tissue nutrient deprivation.¹²²

. Chronic and intermittent hypoxia. Chronically hypoxic cells (left) are

Transiently induced cellular phenotype

It has been shown that intermittent nutrient deprivation can alter the overall cellular phenotype transiently to induce radiation resistance, drug resistance, and metastatic potential.136, 137, 138, 139, 140, 141, 142, 143, 144 In the last few years, there has been an explosion in the knowledge of hypoxia biology. Because of the rapid changes, extent, and complexity of the field, only some of the salient features of hypoxia biology are discussed.

The discovery in the last decade of

The competition model

Clonogenic cell death, the inability of a cell to generate a colony of more than 50 cells, is the most important cellular effect of ionizing radiation.¹⁵⁴ It is the consequence of DNA damage, because irradiation of the cell nucleus is about 100 times more cytotoxic than irradiation of the cell membrane or cytoplasm.¹⁵⁵ The critical DNA lesions are multiple structural alterations within a short segment of the DNA molecule¹⁵⁶ or simply a double-strand break (DSB) in the DNA molecule. The number

The oxygen and sensitizer enhancement ratio

The OER describes the potency of a sensitizer. It is the ratio of the radiation dose required for a given level of cell killing under hypoxic conditions compared with the radiation dose needed in air. The sensitizer enhancement ratio (SER) is a similar concept that mathematically describes the ratio of radiation dose without a sensitizing agent compared with the radiation dose with the agent. The OER will depend on the oxygen concentration, whereas the SER will depend on the sensitizer

Specific modifiers

The number of agents used as modifiers is too extensive to be fully covered in this issue. For many of the historic and theoretical details, the reader is referred to other sources.¹⁷³ Likewise, there are numerous chemotherapy drugs used concurrently with radiation, and it is beyond the scope of this issue to describe each of them in detail. The reader is directed to several excellent reviews on this topic.21, 22, 23, 174 Some of the newer agents that are currently being evaluated include the

Increasing the oxygen content of the blood

To date, the clinical investigations designed to overcome hypoxic cell radioresistance have been largely of two types. Investigators attempt either to increase oxygen delivery or to use oxymimetic radiosensitizers. Methods to increase oxygen delivery have included the use of hyperbaric oxygen,308, 309, 310, 311 carbogen,312, 313 red blood cell transfusions,314, 315 and perfluorocarbons, such as Fluosol-DA.316, 317, 318 The hyperbaric oxygen chamber was the first widely explored approach. Of 9

Specific protectors

Amifostine has been approved for clinical use after a long investigative period initiated by the United States Army radioprotector program. This section will focus on 2 drugs that are chemical radioprotectors, amifostine and Tempol. Growth factors and colony-stimulating factors are used to abrogate myelosuppression, particularly with chemotherapy and combined modality therapy regimens. Cytokines, such as interleukin-1,³⁵⁹ and others such as KGF³⁶⁰ and basic FGF³⁶¹ have been shown to be

Future directions

The advancement in cancer knowledge with strides in tumor, cellular, molecular, and structural biology along with highly innovative techniques such as cDNA microarrays, combinatorial chemistry, and sequencing has produced a vast number of potential new therapeutic targets. There are several themes that may be considered when pondering future strategies:

The macroenvironment of the tumor includes the surrounding normal tissue. This is approached through improved radiation technology such as

Conclusions

There has been a phenomenal increase in new knowledge but limited introduction of new therapies. Amifostine and tirapazamine have been approved, opening up a new approach toward the hypoxic cell. The hypoxic cell sensitizer etanidazole did not provide a therapeutic benefit. Nevertheless, numerous studies indict hypoxia as an important factor in clinical radiation therapy. The next few years will bring exciting changes in cancer biology. With these changes, new developments in radiation and

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To enhance the chemotherapy effect to MDA-MB-231, a glutathione (GSH)-sensitive amphiphilic hyperbranched poly (amide-amine) (mPEG-PLGA-HPAA) was synthesized, and the anti-cancer drug, paclitaxel (PTX) was then encapsulated into the mPEG-PLGA-HPAA micelles. The mPEG-PLGA-HPAA containing a large number of disulfide bonds could degrade and then consume the GSH intracellularly, which was expected to enhances the sensitivity of MDA-MB-231 cells to PTX. It was found that the mPEG-PLGA-HPAA/PTX nanoparticles could respond to the GSH and showed a GSH-controlled PTX release. Simultaneously, the mPEG-PLGA-HPAA/PTX nanoparticles significantly enhanced the efficacy of PTX by inhibiting MDA-MB-231 cells proliferation and inducing cells apoptosis, performing the self-sensitization effect of chemotherapy. Moreover, the drug carrier of mPEG-PLGA-HPAA exhibited excellent biocompatibility in vitro and in vivo. These results indicated that the self-sensitized drug carrier is a promising route to maximize the therapeutic effect and minimize the side effects of chemotherapy drugs used currently in clinical.
Raman spectroscopy demonstrates Amifostine induced preservation of bone mineralization patterns in the irradiated murine mandible
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Adjuvant radiotherapy in the management of head and neck cancer remains severely debilitating. Fortunately, newly developed agents aimed at decreasing radiation-induced damage have shown great promise. Amifostine (AMF) is a compound, which confers radio-protection to the exposed normal tissues, such as bone. Our intent is to utilize Raman spectroscopy to demonstrate how AMF preserves the mineral composition of the murine mandible following human equivalent radiation.
Sprague Dawley rats were randomized into 3 experimental groups: control (n = 5), XRT (n = 5), and AMF–XRT (n = 5). Both XRT and AMF groups underwent bioequivalent radiation of 70 Gy in 5 fractions to the left hemimandible. AMF–XRT received Amifostine prior to radiation. Fifty-six days post-radiation, the hemimandibles were harvested, and Raman spectra were taken in the region of interest spanning 2 mm behind the last molar. Bone mineral and matrix-specific Raman bands were analyzed using one-way ANOVA, with statistical significance at p < 0.05.
The full-width at half-maximum of the primary phosphate band (FWHM) and the ratio of carbonate/phosphate intensities demonstrated significant differences between AMF–XRT versus XRT (p < 0.01) and XRT versus control (p < 0.01). There was no difference between AMF–XRT and control (p > 0.05) in both Raman metrics. Computer‐aided spectral subtraction further confirmed these results where AMF–XRT was spectrally similar to the control. Interestingly, the collagen cross-link ratio did not differ between XRT and AMF–XRT (p < 0.01) but was significantly different from the control (p < 0.01).
Our novel findings demonstrate that AMF prophylaxis maintains and protects bone mineral quality in the setting of radiation. Raman spectroscopy is an emerging and exceptionally attractive clinical translational technology to investigate and monitor both the destructive effects of radiation and the therapeutic remediation of AMF on the structural, physical and chemical qualities of bone.
Potential use of nucleic acid-based agents in the sensitization of nasopharyngeal carcinoma to radiotherapy
2012, Cancer Letters
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However, the use of chemotherapeutic agents and specific modifiers of radiation to enhance the radiation response is complex and frequently causes additional toxicity to patients. The heavy technical demands of effective drug delivery, the uncertainty of optimal timing of agents, and unique physiological micro-environmental conditions of individual patients must be thoroughly investigated before these agents may be used in practice [12]. Short nucleic acid-based cancer therapeutics encompasses a range of agents, including DNAzymes, short interfering RNAs, antisense oligonucleotides, and ribozymes.
Nasopharyngeal carcinoma (NPC) is a highly metastatic cancer. The 2-year survival rate of patients with stage III or IV disease is only about 50%. Due to its high radiosensitivity, radiotherapy is the standard treatment for early-stage of NPC. However, the radioresistance observed in some patients can cause distant metastases and local recurrence after radiotherapy. Special emphasis has been given to the discovery of effective radiosensitizers. Oncogenic proteins encoded by EBV genomes may serve as part of targeted radiosensitization, such as NF кB-mediated expression of latent membrane protein-1. We here review the major nucleic acid-based options currently used in cancer therapeutic approaches and the selected candidate genes that can be targeted for NPC radiosensitization.
Thrombospondin-1 and CD47 limit cell and tissue survival of radiation injury
2008, American Journal of Pathology
Radiation, a primary mode of cancer therapy, acutely damages cellular macromolecules and DNA and elicits stress responses that lead to cell death. The known cytoprotective activity of nitric oxide (NO) is blocked by thrombospondin-1, a potent antagonist of NO/cGMP signaling in ischemic soft tissues, suggesting that thrombospondin-1 signaling via its receptor CD47 could correspondingly increase radiosensitivity. We show here that soft tissues in thrombospondin-1-null mice are remarkably resistant to radiation injury. Twelve hours after 25-Gy hindlimb irradiation, thrombospondin-1-null mice showed significantly less cell death in both muscle and bone marrow. Two months after irradiation, skin and muscle units in null mice showed minimal histological evidence of radiation injury and near full retention of mitochondrial function. Additionally, both tissue perfusion and acute vascular responses to NO were preserved in irradiated thrombospondin-1-null hindlimbs. The role of thrombospondin-1 in radiosensitization is specific because thrombospondin-2-null mice were not protected. However, mice lacking CD47 showed radioresistance similar to thrombospondin-1-null mice. Both thrombospondin-1- and CD47-dependent radiosensitization is cell autonomous because vascular cells isolated from the respective null mice showed dramatically increased survival and improved proliferative capacity after irradiation in vitro. Therefore, thrombospondin-1/CD47 antagonists may have selective radioprotective activity for normal tissues.
Chemical Radiosensitizers for Use in Radiotherapy
2007, Clinical Oncology
Citation Excerpt :
The best-known radioprotector is the thiol prodrug, amifostine* (WR-2721). Activity in this field has been included in other reviews [6,7,9–12] and is not discussed in detail here. The importance of chemical radioprotectors is that their existence illustrates the competition between the enhancement of damage (e.g. by oxygen or drugs) and ‘repair’ in the specific example involving the reaction of short-lived free radicals with thiols, or thiol drugs [6,9].
Radiosensitizers are intended to enhance tumour cell killing while having much less effect on normal tissues. Some drugs target different physiological characteristics of the tumour, particularly hypoxia associated with radioresistance. Oxygen is the definitive hypoxic cell radiosensitizer, the large differential radiosensitivity of oxic vs hypoxic cells being an attractive factor. The combination of nicotinamide to reduce acute hypoxia with normobaric carbogen breathing is showing clinical promise. ‘Electron-affinic’ chemicals that react with DNA free radicals have the potential for universal activity to combat hypoxia-associated radioresistance; a nitroimidazole, nimorazole, is clinically effective at tolerable doses. Hypoxia-specific cytotoxins, such as tirapazamine, are valuable adjuncts to radiotherapy. Nitric oxide is a potent hypoxic cell radiosensitizer; variations in endogenous levels might have prognostic significance, and routes to deliver nitric oxide specifically to tumours are being developed. In principle, many drugs can be delivered selectively to hypoxic tumours using either reductase enzymes or radiation-produced free radicals to activate drug release from electron-affinic prodrugs. A redox-active agent based on a gadolinium chelate is being evaluated clinically. Pyrimidines substituted with bromine or iodine are incorporated into DNA and enhance free radical damage; fluoropyrimidines act by different mechanisms. A wide variety of drugs that influence the nature or repair of DNA damage are being evaluated in conjunction with radiation; it is often difficult to define the mechanisms underlying chemoradiation regimens. Drugs being evaluated include topoisomerase inhibitors (e.g. camptothecin, topotecan), and the hypoxia-activated anthraquinone AQ4N; alkylating agents include temozolomide. Drugs involved in DNA repair pathways being investigated include the potent poly(ADP ribose)polymerase inhibitor, AG14361. Proteins involved in cell signalling, such as the Ras family, are attractive targets linked to radioresistance, as are epidermal growth factor receptors and linked kinases (drugs including vandetanib [ZD6474], cetuximab and gefitinib), and cyclooxygenase-2 (celecoxib). The suppression of radioprotective thiols seems to offer more potential with alkylating agents than with radiotherapy, although it remains a strategy worthy of exploration.
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2007, xPharm: The Comprehensive Pharmacology Reference
WR-1065 is the active form of amifostine (ethyol, WR-2721), a phosphorylated aminothiol prodrug. Amifostine is thought to be dephosphorylated at the tissue site by membrane-bound alkaline phosphatase to WR-1065, which subsequently accumulates in cells. Once inside cells amifostine protects normal tissues from the toxic effects of ionizing radiation and chemotherapeutic agents while either enhancing or having no effect on their antitumor effects …

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^*: Coleman: Director, Radiation Oncology Sciences Program, National Cancer Institute, Bethesda, Maryland

^**: Mitchell: Chief, Radiation Biology Branch, Radiation Oncology Sciences Program, National Cancer Institute, Bethesda, Maryland

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Sensitizers and protectors of radiation and chemotherapy*,**

Abstract

Section snippets

Background

Considerations for modifiers

Combined modality therapy

Radiation sensitizer mechanisms

Clinical trial methodology

Normal tissue toxicity

Hypoxia

Hypoxia summary

Chronic and acute nutrient deprivation and reoxygenation

Transiently induced cellular phenotype

The competition model

The oxygen and sensitizer enhancement ratio

Specific modifiers

Increasing the oxygen content of the blood

Specific protectors

Future directions

Conclusions

Am J Med

Lancet

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Radiother Oncol

Free Radic Biol Med

J Biol Chem

Sem Radia Oncol

Semin Radiat Oncol

Semin Radiat Oncol

Semin Radiat Oncol

Trends Genet

Semin Radiat Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Semin Radiat Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Urology

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Gynecol Oncol

Biochem Biophys Res Commun

Radiother Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Radiation Modifiers

Initial events in the cellular effects of ionizing radiations: clustered damage in DNA

Int J Radiat Biol

Track structure in radiation biology: theory and applications

Int J Radiat Biol

Low-dose radiation sensitivity and induced radioresistance to cell killing in HT-29 cells is distinct from the adaptive response and cannot be explained by a subpopulation of sensitive cells

Radiat Res

Induction of stress genes by low doses of gamma rays

Radiat Res

Current scientific issues related to clinical radiation oncology

Radiat Res

Pilot study of local hyperthermia, radiation therapy, etanidazole, and cisplatin for advanced superficial tumours

Int J Hyperthermia

Radiation and high-dose metronidazole in supratentorial glioblastomas

N Engl J Med

Principles of chemoradiation: theoretical and practical considerations

Oncology

The action of colchicine on cell division in human cancer, animal, and plant tissues

Ann NY Acad Sc

The antileukemic action of combinations of certain known antileukemic agents

Cancer Res

Studies of fluorinated pyrimidines. II. Effects of transplanted tumors

Cancer Res

Combined chemotherapy and irradiation in inoperable bronchogenic carcinoma

Cancer

Treatment of unresectable adenocarcinomas of the stomach with a combination of 5-fluorouracil and radiation

Am J Roentgenol Radium Ther Nucl Med