WK3 - Chemotherapy alkylating agent

What are the 5 classes of alkylating agents?

Nitrogen mustards, Nitrosoureas, Aziridines, Alkyl sulfonates, Monoalkylating agents.

Which alkylating agent can cross the blood-brain barrier?

Carmustine (BCNU) – a nitrosourea.

What is the most commonly used alkylating agent?

Cyclophosphamide (used for breast, lung, lymphoma, many cancers).

What is the history behind nitrogen mustards?

Derived from mustard gas (WWI). Doctors noticed mustard gas caused low white blood cell counts. This led to testing on lymphosarcoma patients.

What happened to the first patient treated with nitrogen mustard?

Lymphosarcoma patient. Tumours shrank within days, but patient died 3 weeks later from leukopenia (low white blood cells).

What is the active intermediate formed by nitrogen mustards?

The aziridinium ion – a positively charged 3-membered ring that is highly reactive.

How does the aziridinium ion form?

A chlorine atom leaves the nitrogen mustard. The nitrogen forms a 3-membered ring with the two carbons, creating a positively charged, strained, reactive ring.

What is the correct direction of attack in alkylation?

The N7 of guanine (which has a lone pair of electrons) attacks the positively charged aziridinium ion. Guanine is the attacker (nucleophile). Aziridinium ion is the target (electrophile).

What specific atom on DNA do alkylating agents target?

The N7 position of guanine.

What is an interstrand crosslink?

A chemical bond that connects the two strands of DNA together. The drug attaches to guanine on one strand and guanine on the opposite strand.

What are the 5 steps of alkylating agent mechanism?

1) First chlorine leaves → first aziridinium ion forms. 2) N7 of guanine (Strand 1) attacks first aziridinium ion. 3) Second chlorine leaves → second aziridinium ion forms. 4) N7 of guanine (Strand 2) attacks second aziridinium ion. 5) Interstrand crosslink forms → DNA cannot separate → replication blocked → cell dies.

Why does an interstrand crosslink kill the cell?

The two DNA strands are glued together. DNA polymerase cannot separate the strands to copy DNA. Replication stops, and the cell dies.

What are the three main mechanisms of resistance to alkylating agents?

1) Increased glutathione and glutathione-S-transferase (neutralise drug). 2) Increased DNA repair enzymes (remove crosslinks). 3) Reduced drug uptake into cells.

What is an aniline mustard?

A nitrogen mustard with a benzene ring attached to the nitrogen. The ring allows control of reactivity.

How does an electron-withdrawing group (e.g., -NO₂) affect aniline mustard reactivity?

Electron-withdrawing pulls electrons away from nitrogen, making aziridinium ion formation slower. The drug becomes LESS reactive.

How does an electron-donating group (e.g., -OCH₃) affect aniline mustard reactivity?

Electron-donating pushes electrons toward nitrogen, making aziridinium ion formation faster. The drug becomes MORE reactive.

What is cisplatin?

A square planar platinum complex discovered by Rosenberg in 1969. Used for testicular (curative), ovarian, head/neck, lung, and bladder cancers.

What is the mechanism of cisplatin activation (aquation)?

A water molecule attacks the platinum centre. This causes a chlorine ligand to leave as Cl⁻. The chlorine is replaced by water, forming a positively charged, reactive aquated platinum complex.

What specific atom on DNA does cisplatin target?

The N7 of guanine (same target as alkylating agents).

What type of crosslink does cisplatin mainly form?

Intrastrand crosslinks (within the same DNA strand). 65% are GpG (two guanines next to each other).

What is the difference between interstrand and intrastrand crosslinks?

Interstrand = between two different DNA strands (alkylating agents). Intrastrand = within the same DNA strand (cisplatin).

How does an intrastrand crosslink kill the cell?

Cisplatin bends the DNA. DNA polymerase cannot move past the bent DNA. Replication stops, and the cell dies.

What is the difference between how alkylating agents and cisplatin kill cells?

Alkylating agents glue two strands together (interstrand) – strands cannot separate. Cisplatin bends one strand (intrastrand) – polymerase cannot pass. Both block replication and kill the cell.

What are the two main mechanisms of resistance to cisplatin?

1) Increased DNA repair enzymes (remove intrastrand crosslinks). 2) Increased glutathione and metallothionein (neutralise drug).

What is the main toxicity of cisplatin?

Nephrotoxicity (kidney damage). Patients must be given fluids to protect their kidneys.

What is the main toxicity of carboplatin?

Bone marrow suppression (less nephrotoxicity than cisplatin).

Which cancer is cisplatin essentially curative for?

Testicular cancer.

What drug is used for CML and what is its target?

Imatinib (Gleevec) – targets BCR-ABL tyrosine kinase.

What is the difference between interstrand and intrastrand crosslinks?

Interstrand = between two strands. Intrastrand = within same strand.

Complete the sentence: "Alkylating agents form ___________ crosslinks. Cisplatin forms ___________ crosslinks.",interstrand / intrastrand

What is the role of glutathione in resistance to alkylating agents?

Glutathione binds to and neutralises alkylating agents before they can reach DNA. Cancer cells with more glutathione are more resistant.

Complete the sentence: "The N7 of guanine attacks the ___________ ion because guanine has a lone pair of ___________ .",aziridinium / electrons

What is the difference between carboplatin and cisplatin?

Carboplatin causes less nausea and less kidney damage, but more bone marrow suppression.