Reactive Nitrogen Species in Carcinogenesis

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Questions and Answers

What is a major source of reactive oxygen species/reactive nitrogen species in irradiated cells?

Radiolysis of water and nitric oxide synthase activation (correct)

Oxidation of fatty acids

Excessive protein degradation

Mitochondrial dysfunction

What effect does peroxynitrite anion (ONOO−) have in cells?

It causes extensive depurinations in DNA (correct)

It enhances the activity of antioxidants

It only reacts with nucleotides

It is chemically inert to cellular targets

Which compound helps to mitigate the damaging effects of free radicals in cells?

Glutathione (correct)

Amifostine

Hydroxyl radical

Peroxynitrite

How are DNA damages from metabolic reactive oxygen species typically characterized compared to radiation-induced damage?

Random distribution versus clustered distribution Signup and view all the answers

What is one role of manganese superoxide dismutase (MnSOD) in the cell?

Converts superoxide radicals into molecular oxygen Signup and view all the answers

What is the significance of thiol-containing drugs like Amifostine in the context of radiotherapy?

They protect normal tissues from radiation damage. Signup and view all the answers

Which type of damage does ionizing radiation specifically target?

DNA primarily Signup and view all the answers

What common characteristic do the reactive oxygen species generated during irradiation and those produced during normal metabolism share?

They have similarities in their generation sources. Signup and view all the answers

Which reactive species is notably produced by the reaction of nitric oxide with superoxide anion?

Peroxynitrite Signup and view all the answers

What cellular process is disrupted when DNA double-strand breaks occur?

Cell-cycle progression Signup and view all the answers

Which phase of the cell cycle involves DNA replication?

S phase Signup and view all the answers

What is the primary role of cyclin-dependent kinases (CDKs) in the cell cycle?

Controlling the order of cell-cycle events Signup and view all the answers

Which of the following CDKs is associated with a diagnostic value in breast cancers?

CDK1 Signup and view all the answers

What pathway is NOT involved in the rejoining of DNA double-strand breaks?

Base excision repair Signup and view all the answers

Which phase of the cell cycle is mitosis followed by cytokinesis?

M phase Signup and view all the answers

What effect does ionizing radiation primarily have when cells are exposed during mitosis?

Induces chromosomal rearrangements Signup and view all the answers

Which checkpoint controls the transition between the G2 and M phases?

G2 checkpoint Signup and view all the answers

What specific role does CDK5 play in cancer pathology?

Plays a role in lung cancer development Signup and view all the answers

Which type of aberrations reflects the cell-cycle phase at the time of irradiation?

Chromosomal aberrations Signup and view all the answers

What is the estimated range of DNA breaks resulting from one gray of absorbed radiation dose?

500 to 1000 single-strand and 25 to 50 double-strand breaks Signup and view all the answers

Which of the following describes local multiply damaged sites (LMDS)?

Clusters of ionizations resulting in complex DNA lesions. Signup and view all the answers

How does high LET irradiation differ from low LET irradiation in terms of DNA damage?

High LET irradiation causes increased numbers and complexities of DNA clustered lesions. Signup and view all the answers

What role do reactive oxygen species (ROS) may play in the cellular response to ionizing radiation?

They activate the ceramide-sphingomyelin pathway, potentially leading to apoptosis. Signup and view all the answers

What is a consequence of chromosomal rearrangements following irradiation?

They may contribute to the carcinogenic properties of ionizing radiation. Signup and view all the answers

What effect do agents that alter protein function have on radiation-induced apoptosis?

They can modify the level of apoptosis, affecting cell survival. Signup and view all the answers

Which of the following factors increase the complexity of DNA clustered lesions?

The presence of reactive oxygen species and high LET irradiation. Signup and view all the answers

Which statement is true about DNA repair pathways in relation to clustered lesions?

Multiple DNA repair pathways likely work together to repair clustered lesions. Signup and view all the answers

What range of ionizations is estimated to occur within a diploid cell per gray of absorbed radiation dose?

Approximately 105 ionizations. Signup and view all the answers

Study Notes

Generation of Reactive Nitrogen Species

Ionizing radiation stimulates inducible nitric oxide synthase (NOS) activity, increasing nitric oxide (NO) production.
NO is chemically inert to most cellular components except heme.
NO reacts with O2 to form peroxynitrite anion (ONOO-).
The peroxynitrite anion is highly reactive, damaging lipids, thiols, proteins, and DNA.
Water radiolysis and early activation of nitric oxide synthases are major sources of reactive oxygen and nitrogen species (ROS/RNS) in irradiated cells, particularly with ambient oxygen present.

ROS/RNS Role in Carcinogenesis

ROS/RNS damage DNA and biomolecules.
Damage can lead to oncogene activation (growth factors) and suppression of tumor genes.
This leads to genetic instability, triggering inflammation, cellular transformation, differentiation, proliferation, and promoting tumor growth.
Angiogenesis, immune response, tissue invasion/metastasis are also affected.
Cell cycle repair and death, specifically apoptosis, senescence, and autophagy, are responses involved in this process.

Endogenous and Radiation-Induced DNA Alterations

Endogenous biochemical processes contribute significantly to genome mutations.
ROS produced during normal metabolic processes (especially O2 and H2O2) cause extensive depurination and depyrimidination.
Radiation-induced ROS are similar to metabolically generated ROS in their overall spectrum.
However, radiation-induced DNA damage clusters more frequently than metabolically-induced damage.

Cellular Antioxidants

Cells contain naturally occurring thiol compounds (e.g., glutathione, cysteine, cysteamine, and metallothionein).
Sulfhydryl (SH) groups in these compounds can react with free radicals, lessening their damage.
Other key antioxidants include vitamins C and E and intracellular manganese superoxide dismutase (MnSOD).
MnSOD catalyzes superoxide radicals into more stable molecular oxygen (02).

Intracellular Thiols and Antioxidants in Radiotherapy

Intracellular thiols and antioxidant levels differ between normal and tumor tissues.
Manipulating these levels may protect normal tissues from radiotherapy damage.
Amifostine, a thiol-containing drug, protects against radiation-induced xerostomia (dry mouth) after salivary gland irradiation.

DNA Damage by Ionizing Radiation

The random nature of energy deposition during irradiation means damage can occur in any cell molecule.
DNA is a primary target due to its biological importance.
Even small amounts of DNA damage can cause cell death (lethality).
Estimated ionization events in a typical diploid cell following irradiation are in the 105 range per Gray (unit of absorbed radiation dose).
Different types of DNA damage include cross-links, damaged bases, single-strand breaks, and double-strand breaks.
Most ionization events do not result in DNA damage.

Focal Areas of DNA Damage

"Local multiply damaged sites" (LMDS) arise from the clustering of ionizations within a few nanometers of DNA.
Combinations of single- or double-strand breaks, altered or lost bases, and DNA-DNA or DNA-protein crosslinks are features of these sites.
Repair mechanisms struggle with clustered lesions.
High LET (Linear Energy Transfer) irradiation causes more complex and numerous clustered lesions, making repair more challenging.

Cell Cycle and Irradiation

The cell cycle has specific phases (G1, S, G2, M).
Irradiation in different phases results in varying mitotic delays.
Cells irradiated during specific phases experience more significant cell death rates as compared to others.
Cell cycle progression is regulated by cyclin-dependent kinases (CDKs).

Immunohistochemical Study of Cyclin-Dependent Kinases (CDKs)

CDK1 is important in diagnosing esophageal and breast cancers.
CDK5 is linked to lung cancers while CDK6 is implicated in ovarian cancer.
These findings have implications in the treatment and diagnosis strategy.

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Description

Explore the role of reactive nitrogen species (RNS) and reactive oxygen species (ROS) in the process of carcinogenesis. This quiz covers how ionizing radiation affects nitric oxide production and leads to DNA damage, oncogene activation, and tumor progression. Test your knowledge on the mechanisms involved in these complex biological processes.