Reactive Nitrogen Species and Carcinogenesis

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Questions and Answers

What are the main pathways for rejoining DNA double-strand breaks in mammalian cells?

The main pathways are homologous recombination and non-homologous end-joining.

During which phase of the cell cycle does DNA replication occur and what specifically happens to the chromosomes?

DNA replication occurs during the S phase, where each of the 56 chromosomes (23 pairs) is replicated.

What role do cyclin-dependent kinases (CDKs) play in the cell cycle?

CDKs are involved in controlling cell cycle progression by ensuring the correct order of cell-cycle events.

What can be inferred about the pattern of mitotic delay observed when cells are irradiated at different phases of the cell cycle?

The mitotic delay observed is dependent on the radiation dose and the specific phase of the cell cycle at which the cells are irradiated. Signup and view all the answers

What is the significance of CDK1, CDK5, and CDK6 regarding cancer pathology?

CDK1 is linked with esophageal and breast cancers, CDK5 with lung cancer, and CDK6 has been found misexpressed in ovarian cervical cancer. Signup and view all the answers

How does ionizing radiation influence nitric oxide synthase (NOS) activity?

Ionizing radiation stimulates inducible nitric oxide synthase (NOS) activity, leading to the generation of significant amounts of nitric oxide (NO). Signup and view all the answers

What is the chemical reaction that occurs between nitric oxide (NO) and superoxide ($O_2^{ullet-}$)?

Nitric oxide (NO) reacts with superoxide ($O_2^{ullet-}$) to form the peroxynitrite anion (ONOO$^{-}$). Signup and view all the answers

What is a major source of reactive oxygen species (ROS) in irradiated cells?

The radiolysis of water and early activation of nitric oxide synthases are major sources of ROS in irradiated cells under ambient oxygen. Signup and view all the answers

How do the effects of endogenous ROS differ from those of radiation-induced ROS on DNA?

Endogenous ROS damage DNA randomly, while radiation-induced ROS typically cause clustered DNA damage. Signup and view all the answers

What role does manganese superoxide dismutase (MnSOD) play in cellular defense?

MnSOD catalyzes the conversion of the superoxide radical ($O_2^{ullet-}$) into ordinary molecular oxygen ($O_2$). Signup and view all the answers

How might manipulating intracellular levels of thiols and antioxidative molecules serve as a clinical strategy?

Manipulating these levels may protect normal tissues from radiation-induced damage during therapies like radiotherapy. Signup and view all the answers

What is the significance of DNA as a target for ionizing radiation?

DNA is a major target because imbalances in its integrity can result in cell lethality, affecting overall cellular function. Signup and view all the answers

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

Approximately 105 ionizations per gray. Signup and view all the answers

Identify two types of DNA damage caused by ionization events as mentioned in the content.

Single-strand breaks and double-strand breaks. Signup and view all the answers

Explain what local multiply damaged sites (LMDS) refer to in the context of DNA damage.

LMDS refer to combinations of single- or double-strand breaks and other DNA lesions clustered in close proximity. Signup and view all the answers

What impact does high LET irradiation have on DNA clustered lesions compared to low LET?

High LET irradiation increases both the number and complexity of DNA clustered lesions. Signup and view all the answers

How do reactive oxygen species (ROS) induced by ionizing radiation affect cells?

ROS can interact with cell membrane proteins, potentially leading to apoptosis. Signup and view all the answers

What role do ceramide-sphingomyelin pathways play in radiation-induced cell death?

They are activated in the membrane and can lead to apoptosis in certain cell types. Signup and view all the answers

Mention one way that preincubation with certain agents can modify radiation effects.

It can alter the level of radiation-induced apoptosis. Signup and view all the answers

What type of chromosomal rearrangements can be found in human cancers related to ionizing radiation?

Chromosomal translocations, deletions, and amplifications. Signup and view all the answers

How is chromosomal instability after irradiation demonstrated according to the content?

By observing chromosomal rearrangements post-irradiation. Signup and view all the answers

What two cellular regions interact with ionizing radiation damage as discussed in the text?

The plasma membrane and nucleus. Signup and view all the answers

Study Notes

Generation of Reactive Nitrogen Species

Ionizing radiation stimulates inducible nitric oxide synthase (NOS) activity, producing large amounts of nitric oxide (NO).
NO is chemically inert towards most cellular components, except heme.
NO reacts with oxygen (O2) to form peroxynitrite anion (ONOO⁻).
Peroxynitrite anion is highly reactive and damages lipids, thiols, proteins, and DNA.
Water radiolysis and early nitric oxide synthase activation are significant sources of reactive oxygen and nitrogen species (ROS/RNS) in irradiated cells.

ROS/RNS Role in Carcinogenesis

ROS/RNS damage DNA and biomolecules.
This leads to oncogene activation, tumour gene suppression, genetic instability, and inflammation.
Cellular transformation, differentiation, proliferation, and apoptosis are affected.
Tumor promotion, angiogenesis, immune response, tissue invasion, and metastasis are observed outcomes.
Cell cycle repair and cell death via apoptosis, senescence, and autophagy are involved.

Endogenous and Radiation-Induced DNA Alterations

Endogenous biochemical processes significantly contribute to genome mutations.
ROS produced during normal cellular metabolic processes (mainly O2 and H2O2 cause extensive depurinations and, to a lesser extent, depyrimidinations).
Radiation-induced ROS have a similar spectrum to that produced by metabolic processes, but differ in microdistribution in the cell.
Radiation-induced DNA damage tends to cluster, unlike metabolic ROS damage.

Cell Defence Mechanisms (Antioxidants)

Cells possess naturally occurring thiol compounds (e.g., glutathione, cysteine, cysteamine, and metallothionein).
These thiol compounds react with free radicals, reducing their damaging effects.
Other antioxidants include vitamins C and E and intracellular manganese superoxide dismutase (MnSOD).
MnSOD catalyzes the conversion of superoxide radical (O₂⁻) into molecular oxygen (O₂).

Intracellular Thiol and Antioxidative Molecules

Normal and tumour tissues may exhibit differing intracellular levels of thiols and antioxidative molecules.
Manipulation of these molecules might protect normal tissues from radiotherapy-induced damage.
Amifostine, a thiol-containing drug, can prevent radiotherapy-induced xerostomia (dry mouth) after salivary gland irradiation.

DNA Damage by Ionizing Radiation

The random nature of energy deposition in cells by ionizing radiation means any molecule, including DNA, can be affected.
DNA is a prime target because of its crucial biological functions.
Even small amounts of DNA damage can lead to cell lethality.
Ionizing radiation can cause DNA–DNA or DNA–protein crosslinks, damage to DNA bases, and single- and double-strand DNA breaks.
Most ionizations do not cause DNA damage.
Ionizations cluster in specific regions.

Focal DNA Damage

DNA damage occurs in clusters (Local Multiply-Damaged Sites, LMDS).
LMDS include clustered single/double strand breaks in sugar-phosphate backbone and base alterations/loss.
Crosslinks between DNA strands or between DNA/chromosomal proteins are also formed.
High LET irradiation promotes DNA cluster lesions which are harder to repair after radiation.

Cell Cycle and Ionizing Radiation

The cell cycle comprises G₁ (growth), S (synthesis), G₂ (growth), and M (mitosis).
Ionizing radiation affects cell cycle progression, causing delays in mitosis progress at each phase.
Cell cycle checkpoints are regulated by molecular checkpoints (genes) to ensure correct cell cycle progression.
These checkpoints ensure processes are completed before the cell cycle proceeds.
Cyclin-dependent kinases (CDKs) control progression through the cell cycle.

Immunohistochemistry and Cell Cycle Proteins

Immunohistochemistry (IHC) studies of cyclin-dependent kinases (CDKs) show diagnostic value for esophageal and breast cancers.
CDK5 plays a role in lung cancer; CDK6 is mis-expressed in ovarian cervical cancer.
CDK5 and CDK6 expressions are relevant in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

Radiation Effects on Cell Cycle Progression

Cells irradiated during varied phases of the cell cycle exhibit different patterns of mitotic delays and survivals.
The progression to mitosis following irradiation is altered based on the specific radiation dose to corresponding phase of the cell cycle.
Survival curves show differing effects for cells at varied phases of the cell cycle.

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Description

This quiz explores the generation of reactive nitrogen species and their role in cancer development. It covers how ionizing radiation stimulates nitric oxide production and the subsequent cellular damage caused by reactive species. Dive into the mechanisms of DNA damage, oncogene activation, and the consequences on tumor biology.