Nucleic Acids 1 - Sha

What is the primary target of DNA-interactive anticancer drugs?

"DNA, which is nucleophilic, making it a good target for electrophilic molecules in anticancer drugs."

What are the types of DNA adducts formed by anticancer drugs?

"Topoisomerase adducts, interstrand cross-links, intrastrand cross-links, DNA cleavage, intercalation, and mono-adducts."

How does selective toxicity of anticancer drugs arise?

"Due to differences in growth rates of cancer cells compared to normal cells, reduced DNA repair in cancer cells, and targeting specific DNA regions prevalent in tumours."

What role does the p53 transcription factor play in cancer?

"p53 regulates DNA repair enzymes and engages apoptosis in response to DNA damage, preventing mutation accumulation."

What are the short-term side effects of DNA-interactive anticancer agents?

"Hair loss, GI toxicity, nausea, and myelosuppression."

What is the mechanism of action of methylating agents like dacarbazine?

"They methylate guanine bases in the major groove of DNA, predominantly at N7 and O6 positions, causing genotoxic stress."

What is temozolomide used to treat?

"Glioblastoma, due to its good bioavailability and CNS penetration."

How does temozolomide selectively target cancer cells?

"It requires tumour cells to be MMR proficient and deficient in MGMT (a DNA repair enzyme), ensuring methylation damage is not repaired."

What distinguishes ET-743 from other DNA-binding agents?

"ET-743 forms bulky adducts in the minor groove, bending DNA towards the major groove, unlike other agents that bend DNA away."

What are the two types of nitrogen mustards?

"Aliphatic nitrogen mustards (highly reactive) and aromatic nitrogen mustards (less reactive due to an electron-sink aromatic ring)."

How do nitrogen mustards cause DNA damage?

"They form interstrand cross-links by covalently binding to guanine in the major groove, blocking replication and transcription."

What are the resistance mechanisms to nitrogen mustards?

"Overexpression of MDR pumps, increased glutathione levels, and enhanced DNA repair processes in cancer cells."

What is the advantage of aromatic nitrogen mustards like melphalan?

"They are less reactive and can be administered orally, reducing side effects and toxicity."

How does mitomycin C selectively target cancer cells?

"It requires a bioreductive step facilitated by the hypoxic environment in tumour cores, activating its DNA cross-linking properties."

What are the clinical uses of nitrosoureas like carmustine and lomustine?

"They are used to treat brain tumours, myeloma, and lymphoma due to their lipophilicity and CNS penetration."

What is the dose-limiting toxicity of nitrosoureas?

"Severe bone marrow toxicity, which can be permanent and lethal."

What is the mechanism of action of methanesulfonates like busulphan?

"They form DNA cross-links, with methanesulfonyl oxy moieties acting as leaving groups after nucleophilic attack on DNA."

How do aziridines differ from nitrogen mustards in their mechanism?

"Aziridines directly attack N7 in the major groove without undergoing internal cyclisation, as their reactive groups are pre-formed."

What is the significance of the MGMT enzyme in temozolomide therapy?

"Low or absent MGMT activity in tumour cells prevents repair of methylated guanine, enhancing temozolomide's cytotoxic effects."

What are the long-term effects of DNA-interactive anticancer agents?

"Fertility loss and potential permanent bone marrow damage."

How does the hypoxic environment in tumours aid mitomycin C's action?

"Hypoxia provides a reducing environment that activates mitomycin C, making it selective for tumour cells."

What is the role of MMR enzymes in temozolomide's mechanism?

"MMR enzymes attempt to repair methylated guanine, introducing additional mutations that lead to genotoxic stress and cell death."

Why are nitrosoureas effective against brain tumours?

"Their high lipophilicity allows them to penetrate the blood-brain barrier and target cancer cells in the CNS."

What is the primary toxicity of melphalan?

"Bone marrow toxicity, requiring administration at six-week intervals to mitigate risks like prolonged neutropenia."

How do cross-linking agents like nitrogen mustards block DNA replication?

"They form covalent bonds between DNA strands (interstrand cross-links), preventing strand separation and replication."