Chemical modifiers of cancer treatment.

Chemical modification is a concept in cancer therapy in which the state of tumor cells or normal tissues is modified such that a therapeutic gain can be achieved using conventional therapeutic modalities. Hypoxic zones targeted as cells within them may be radiation resistant, poorly perfused by chemotherapeutic agents, and possibly drug resistant due to hypoxia-related gene amplification. Nitroimidazoles have gained particular attention as chemical modifiers because they can increase the radiation sensitivity of hypoxic cells, are cytotoxic to hypoxic cells, can increase sensitivity to chemotherapeutic agents, and are useful for imaging hypoxic cells. While both radiosensitization and chemosensitization require hypoxia, the mechanism of the enhancement of each of the modalities is different. The 2-nitroimidazole hypoxic sensitizers SR 2508 and Ro-03-8799, which are less toxic than the prototype misonidazole (Miso), are in clinical trials, and dual function molecules that include a hypoxic sensitizer and alkylating function are being developed. The presence of both acutely and chronically hypoxic cells in animal tumors has been demonstrated by new imaging techniques. Oxygen delivery to tumors is being altered by the use of perfluorocarbons, and agents that alter hemoglobin affinity for oxygen. Compounds that are selectively toxic to hypoxic cells are being developed. Nonhypoxic modifiers are also being investigated. Thiol modification, particularly the alteration of glutathione concentration, has complex effects on the cell's biochemistry, in addition to affecting the competition between oxygen and thiol groups for the restoration and fixation of radiation-induced radicals. WR-2721 is being studied as a means of reducing the normal tissue toxicity of radiation and chemotherapy. Increased thiol concentration may be a mechanism of cross-resistance between certain chemotherapeutic agents and radiation.

Download Full-text

Repair of gamma-ray-induced base damage in L5178Y sublines is damage type-dependent and unrelated to radiation sensitivity.

Acta Biochimica Polonica ◽

10.18388/abp.2001_3935 ◽

2001 ◽

Vol 48 (2) ◽

pp. 525-533 ◽

Cited By ~ 1

Author(s):

M Kruszewski ◽

T H Zastawny ◽

I Szumiel

Keyword(s):

Ionizing Radiation ◽

Gamma Ray ◽

Radiation Sensitivity ◽

Dna Double Strand Breaks ◽

Base Damage ◽

Modified Dna ◽

Radiation Resistant ◽

Radiation Induced ◽

Gamma Irradiated ◽

Mutagenic Effects

The L5178Y (LY) murine lymphoma sublines LY-R and LY-S are differentially sensitive to ionizing radiation. The high radiation sensitivity of LY-S cells is related to impaired rejoining of DNA double strand breaks. We found previously that the gamma-ray-induced base damage is higher in the more radiosensitive LY-S subline. Here, we examine the role of the repair of ionizing radiation induced base damage in relation to the radiosensitivity difference of these sublines. We used the GS/MS technique to estimate the repair rates of six types of base damage in gamma-irradiated LY cells. All modified DNA bases identified in the course of this study were typical for irradiated chromatin. The total amount of initial base damage was higher in the radiation sensitive LY-S subline than in the radiation resistant LY-R subline. The repair rates of 5-OHMeUra, 5-OHCyt, 8-OHAde were similar in both cell lines, the repair rates of FapyAde and 8-OHGua were higher in the radiosensitive LY-S cell line, whereas the repair of 5-OHUra was faster in its radioresistant counter, the LY-R. Altogether, the repair rates of the y-ray-induced DNA base damage in LY sublines are related neither to the initial amounts of the damaged bases nor to the differential lethal or mutagenic effects of ionizing radiation in these sublines.

Download Full-text

Cardiotoxicity of Cancer Therapy

Journal of Clinical Oncology ◽

10.1200/jco.2005.08.789 ◽

2005 ◽

Vol 23 (30) ◽

pp. 7685-7696 ◽

Cited By ~ 214

Author(s):

Justin D. Floyd ◽

Duc T. Nguyen ◽

Raymond L. Lobins ◽

Qaiser Bashir ◽

Donald C. Doll ◽

...

Keyword(s):

Cancer Therapy ◽

Adverse Effects ◽

Antineoplastic Agents ◽

The United States ◽

Chemotherapeutic Agents ◽

Therapeutic Modalities ◽

Normal Tissues ◽

Neoplastic Processes ◽

Multiple Organs ◽

Number Of Patients

Because cancer is a leading cause of mortality in the United States, the number of therapeutic modalities available for the treatment of neoplastic processes has increased. This has resulted in a large number of patients being exposed to a wide variety of cancer therapy. Historically, it has been well recognized that antineoplastic agents may have adverse effects on multiple organs and normal tissues. The most commonly associated toxicities occur in tissues composed of rapidly dividing cells and may spontaneously reverse with minimal long-term toxicity. However, the myocardium consists of cells that have limited regenerative capability, which may render the heart susceptible to permanent or transient adverse effects from chemotherapeutic agents. Such toxicity encompasses a heterogeneous group of disorders, ranging from relatively benign arrhythmias to potentially lethal conditions such as myocardial ischemia/infarction and cardiomyopathy. In some instances, the pathogenesis of these toxic effects has been elucidated, whereas in others the precise etiology remains unknown. We review herein the various syndromes of cardiac toxicity that are reported to be associated with antineoplastic agents and discuss their putative mechanisms and treatment.

Download Full-text

Long non-coding RNAs as the critical regulators of doxorubicin resistance in tumor cells

Cellular & Molecular Biology Letters ◽

10.1186/s11658-021-00282-9 ◽

2021 ◽

Vol 26 (1) ◽

Author(s):

Ghazaleh Khalili-Tanha ◽

Meysam Moghbeli

Keyword(s):

Drug Resistance ◽

Cancer Patients ◽

Clinical Outcomes ◽

Topoisomerase Ii ◽

Tumor Therapy ◽

Chemotherapeutic Agents ◽

Cancer Drug ◽

Therapeutic Modalities ◽

Normal Tissues ◽

Non Coding Rnas

AbstractResistance against conventional chemotherapeutic agents is one of the main reasons for tumor relapse and poor clinical outcomes in cancer patients. Various mechanisms are associated with drug resistance, including drug efflux, cell cycle, DNA repair and apoptosis. Doxorubicin (DOX) is a widely used first-line anti-cancer drug that functions as a DNA topoisomerase II inhibitor. However, DOX resistance has emerged as a large hurdle in efficient tumor therapy. Furthermore, despite its wide clinical application, DOX is a double-edged sword: it can damage normal tissues and affect the quality of patients’ lives during and after treatment. It is essential to clarify the molecular basis of DOX resistance to support the development of novel therapeutic modalities with fewer and/or lower-impact side effects in cancer patients. Long non-coding RNAs (lncRNAs) have critical roles in the drug resistance of various tumors. In this review, we summarize the state of knowledge on all the lncRNAs associated with DOX resistance. The majority are involved in promoting DOX resistance. This review paves the way to introducing an lncRNA panel marker for the prediction of the DOX response and clinical outcomes for cancer patients.

Download Full-text

High-resolution topographic SEM and radiation damage: The rationale for using low beam voltage

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100131024 ◽

1992 ◽

Vol 50 (2) ◽

pp. 1278-1279

Author(s):

James Pawley ◽

David Joy

Keyword(s):

High Resolution ◽

Imaging Techniques ◽

Morphological Structure ◽

Radiation Sensitivity ◽

Beam Specimen ◽

Measured Signal ◽

Practical Consideration ◽

Interaction Volume ◽

Impact Area ◽

Signal Contrast

The scanning electron microscope (SEM) builds up an image by sampling contiguous sub-volumes near the surface of the specimen. A fine electron beam selectively excites each sub-volume and then the intensity of some resulting signal is measured and then plotted as a corresponding intensity in an image. The spatial resolution of such an image is limited by at least three factors. Two of these determine the size of the interaction volume: the size of the electron probe and the extent to which detectable signal is excited from locations remote from the beam impact area. A third limitation emerges from the fact that the probing beam is composed of a number of discrete particles and therefore that the accuracy with which any detectable signal can be measured is limited by Poisson statistics applied to this number (or to the number of events actually detected if this is smaller). As in all imaging techniques, the limiting signal contrast required to recognize a morphological structure is constrained by this statistical consideration. The only way to overcome this limit is to increase either the contrast of the measured signal or the number of beam/specimen interactions detected. Unfortunately, these interactions deposit ionizing radiation that may damage the very structure under investigation. As a result, any practical consideration of the high resolution performance of the SEM must consider not only the size of the interaction volume but also the contrast available from the signal producing the image and the radiation sensitivity of the specimen.

Download Full-text

Investigation of Cross-resistance to a Range of Photosensitizers, Hyperthermia and UV Light in Two Radiation-induced Fibrosarcoma Cell Strains Resistant to Photodynamic Therapy In Vitro¶

Photochemistry and Photobiology ◽

10.1562/0031-8655(2001)073<0039:iocrta>2.0.co;2 ◽

2001 ◽

Vol 73 (1) ◽

pp. 39 ◽

Cited By ~ 12

Author(s):

Stephen Mayhew ◽

David I. Vernon ◽

Jack Schofield ◽

John Griffiths ◽

Stanley B. Brown

Keyword(s):

Photodynamic Therapy ◽

Uv Light ◽

Cross Resistance ◽

Fibrosarcoma Cell ◽

Radiation Induced ◽

Cell Strains

Download Full-text

Cytoprotective Agents to Avoid Chemotherapy Induced Sideeffects on Normal Cells: A Review

Current Cancer Drug Targets ◽

10.2174/1568009619666190326120457 ◽

2019 ◽

Vol 19 (10) ◽

pp. 765-781

Author(s):

Seema Rohilla ◽

Harish Dureja ◽

Vinay Chawla

Keyword(s):

Adverse Effects ◽

Anticancer Agents ◽

Therapeutic Index ◽

Chemotherapeutic Agents ◽

Vital Role ◽

Normal Cells ◽

Normal Tissues ◽

Organ Specific ◽

Delay In Treatment

Anticancer agents play a vital role in the cure of patients suffering from malignancy. Though, the chemotherapeutic agents are associated with various adverse effects which produce significant toxic symptoms in the patients. But this therapy affects both the malignant and normal cells and leads to constricted therapeutic index of antimalignant drugs which adversely impacts the quality of patients’ life. Due to these adversities, sufficient dose of drug is not delivered to patients leading to delay in treatment or improper treatment. Chemoprotective agents have been developed either to minimize or to mitigate the toxicity allied with chemotherapeutic agents. Without any concession in the therapeutic efficacy of anticancer drugs, they provide organ specific guard to normal tissues.

Download Full-text

Hyperthermic Intraperitoneal Chemotherapy: A Critical Review

Cancers ◽

10.3390/cancers13133114 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3114

Author(s):

Wim Ceelen ◽

Jesse Demuytere ◽

Ignace de Hingh

Keyword(s):

Intraperitoneal Chemotherapy ◽

Imaging Techniques ◽

Systemic Exposure ◽

Theoretical Concept ◽

Chemotherapeutic Agents ◽

Peritoneal Metastases ◽

Attractive Alternative ◽

True Value ◽

Heated Intraperitoneal Chemotherapy ◽

Study Results

With increasing awareness amongst physicians and improved radiological imaging techniques, the peritoneal cavity is increasingly recognized as an important metastatic site in various malignancies. Prognosis of these patients is usually poor as traditional treatment including surgical resection or systemic treatment is relatively ineffective. Intraperitoneal delivery of chemotherapeutic agents is thought to be an attractive alternative as this results in high tumor tissue concentrations with limited systemic exposure. The addition of hyperthermia aims to potentiate the anti-tumor effects of chemotherapy, resulting in the concept of heated intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal metastases as it was developed about 3 decades ago. With increasing experience, HIPEC has become a safe and accepted treatment offered in many centers around the world. However, standardization of the technique has been poor and results from clinical trials have been equivocal. As a result, the true value of HIPEC in the treatment of peritoneal metastases remains a matter of debate. The current review aims to provide a critical overview of the theoretical concept and preclinical and clinical study results, to outline areas of persisting uncertainty, and to propose a framework to better define the role of HIPEC in the treatment of peritoneal malignancies.

Download Full-text

Coexistence of SOS-Dependent and SOS-Independent Regulation of DNA Repair Genes in Radiation-Resistant Deinococcus Bacteria

Cells ◽

10.3390/cells10040924 ◽

2021 ◽

Vol 10 (4) ◽

pp. 924

Author(s):

Laurence Blanchard ◽

Arjan de Groot

Keyword(s):

Dna Repair ◽

Deinococcus Radiodurans ◽

Dna Repair Genes ◽

Lesion Bypass ◽

Radiation Resistant ◽

Radiation Induced ◽

Induced Mutagenesis ◽

High Doses ◽

Translesion Polymerases ◽

Repair Genes

Deinococcus bacteria are extremely resistant to radiation and able to repair a shattered genome in an essentially error-free manner after exposure to high doses of radiation or prolonged desiccation. An efficient, SOS-independent response mechanism to induce various DNA repair genes such as recA is essential for radiation resistance. This pathway, called radiation/desiccation response, is controlled by metallopeptidase IrrE and repressor DdrO that are highly conserved in Deinococcus. Among various Deinococcus species, Deinococcus radiodurans has been studied most extensively. Its genome encodes classical DNA repair proteins for error-free repair but no error-prone translesion DNA polymerases, which may suggest that absence of mutagenic lesion bypass is crucial for error-free repair of massive DNA damage. However, many other radiation-resistant Deinococcus species do possess translesion polymerases, and radiation-induced mutagenesis has been demonstrated. At least dozens of Deinococcus species contain a mutagenesis cassette, and some even two cassettes, encoding error-prone translesion polymerase DnaE2 and two other proteins, ImuY and ImuB-C, that are probable accessory factors required for DnaE2 activity. Expression of this mutagenesis cassette is under control of the SOS regulators RecA and LexA. In this paper, we review both the RecA/LexA-controlled mutagenesis and the IrrE/DdrO-controlled radiation/desiccation response in Deinococcus.

Download Full-text

Synthesis and characterization of a new series of thiadiazole derivatives as potential anticancer agents

Heterocyclic Communications ◽

10.1515/hc-2020-0002 ◽

2020 ◽

Vol 26 (1) ◽

pp. 6-13 ◽

Cited By ~ 1

Author(s):

Ulviye Acar Çevik ◽

Derya Osmaniye ◽

Serkan Levent ◽

Begüm Nurpelin Sağlik ◽

Betül Kaya Çavuşoğlu ◽

...

Keyword(s):

Anticancer Agents ◽

Biological Activities ◽

Cancer Cell Line ◽

Chemotherapeutic Agents ◽

Anticancer Activities ◽

Normal Tissues ◽

H Nmr ◽

Wide Range ◽

Thiadiazole Derivatives ◽

Low Efficiency

AbstractCancer is one of the most common causes of death in the world. Despite the importance of combating cancer in healthcare systems and research centers, toxicity in normal tissues and the low efficiency of anticancer drugs are major problems in chemotherapy. Nowadays the aim of many medical research projects is to discover new safer and more effective anticancer agents. 1,3,4-Thiadiazole compounds are important fragments in medicinal chemistry because of their wide range of biological activities, including anticancer activities. The aim of this study was to determine the capacity of newly synthesized 1,3,4-thiadiazole compounds as chemotherapeutic agents. The structures of the obtained compounds were elucidated using 1H-NMR, 13C-NMR and mass spectrometry. Although the thiadiazole derivatives did not prove to be significantly cytotoxic to the tumour tissue cultures, compound 4i showed activity against the C6 rat brain cancer cell line (IC50 0.097 mM) at the tested concentrations.

Download Full-text