bleomycin mechanism of action

[ChessMaster3000]

I've done a little research and there is a ton of conflicting information for the MOA of bleomycin. I am sure it has multiple effects on DNA, leading to the confusion. For TESTING purposes, what would you say the most important mechanism of action is?

RR Biochem says that it inhibits topoisomerase II like etoposide. Elsewhere I have read it "blows my DNA to bits" (BLeoMYcin), which I interpret as an intercalating agent. It could also be an alkylating agent given that description. I'm inclined to lean towards intercalating agent, but I really don't know. Also, would this affect the G2 phase?

Many thanks in advance.

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[notbobtrustme]

I'm going with bleomycin damages DNA through free radical generation. It's not really cell cycle specific because getting your DNA blowed up will kill you.

 

[MudPhud20XX]

According to both FA and Kaplan pharm, bleomycin is G2 specific.

Kaplan pharm says: bleomycin complexes with Fe and O2, which leads to DNA strand scission (G2 phase), which is most likely as a result of the oxidative stress.

Though I'm not sure how this would be specific to G2, which is basically a phase before mitotic division.

Also, the MOA of bleomycine seems to be related to the fact that one the major side effects of bleomycin is pulmonary fibrosis. Wiki says that bleomycin induced lung injury is associated with the oxygen toxicity in the lung.

I doubt that we need to know the detailed mechanism, but we probably should know that it's G2 specific and the main side effect is pulomonary fibrosis.

Has anyone seen questions asking MOA of bleomycin is G2 specific form Q bank?

 

[ChessMaster3000]

According to both FA and Kaplan pharm, bleomycin is G2 specific.

Kaplan pharm says: bleomycin complexes with Fe and O2, which leads to DNA strand scission (G2 phase), which is most likely as a result of the oxidative stress.

Though I'm not sure how this would be specific to G2, which is basically a phase before mitotic division.

Also, the MOA of bleomycine seems to be related to the fact that one the major side effects of bleomycin is pulmonary fibrosis. Wiki says that bleomycin induced lung injury is associated with the oxygen toxicity in the lung.

I doubt that we need to know the detailed mechanism, but we probably should know that it's G2 specific and the main side effect is pulomonary fibrosis.

Has anyone seen questions asking MOA of bleomycin is G2 specific form Q bank?

I havent yet, but I am anticipating it will come up. I think the fact that bleomycin lung injury is associated with oxygen toxicity, along with the fact that it complexes with fe and o2 (according to Kaplan), means that this is a free radical-associated mechanism.

 

[Transposony]

Bleomycin binds to guanosine-cytosine-rich portions of DNA via association of the "S" tripeptide and by partial intercalation of the bithiazole rings. A group of five nitrogen atoms arranged in a square-pyramidal conformation binds divalent metals including iron, the active ligand, and copper, an inactive ligand. Molecular oxygen, bound by the iron, can produce highly reactive free radicals and Fe(III). The free radicals produce DNA single-strand breaks at 3'-4' bonds in deoxyribose. This yields free base propenals, especially of thymine: cytotoxicity is cell-cycle-phase specific for G2 phase.

Radiation and chemical reactions that give rise to free radicals cause the formation of highly cytotoxic base propenals, degradation products of DNA.

Resistance to bleomycin in normal tissues can be correlated with the presence of a bleomycin hydrolase enzyme, which is in the cysteine proteinase family. The enzyme replaces a terminal amine with a hydroxyl, thereby inhibiting iron binding and cytotoxic activity. The low concentration of enzyme in the skin and lung may explain the unique sensitivity of these tissues to bleomycin toxicity.