Medications
Attaches to DNA with Fe as a chelate and cleaves one side of the DNA
Bleomycin/Blenoxane
Fundamentals:
Mechanism:
- Chelation w/ Fe increases affinity for one side of DNA - Worth et al 1993 Scheme 1 (no captions how specifically)
Initiation
- C4 Hydrogen is attacked by the activated BM (best guess is that
the activation creates a strong NUC in basic conditions of nucleus)
- sp3 radical formed
- Homolytic cleavage
Propagation
- 1)Oxygen dependent - neutral conditions
- Formation of 3'phosphoglycolate terminus and nucleic acid base propenal
- O2 attacks the C4 radical creating a O-O* radical at the C4
- This radical is protonated (by the initial H* homolytic cleaved?) - Termination
- HO-O has a leaving group attached to it and since the pH of the nucleus is higher 7.5+ish
- The surroundings are basic so this HO- is not that bad of a leaving group
- Furthermore it allows the formation of a carbonyl after ring opening
- Ring opening of the epoxide is base catalyzed and attacks the anomeric carbon C1
- C3 has a phosphate group with an O-PO3 so the resonance of the O attached to the C3 would have a partial double bond character
- Makes it prone to a nucleophilic attack
- Releases the phosphate (one of the observed products)
- This would help influence a reversible carbonyl formation on
the C4 that received electrons for the previous base catalyzed epoxide
ring opening
- Releases the NitrogenousBase-1,2,3 portion of the ribose (OH in the 1 and 3 positions)
- In basic conditions I would imagine that the C3 is deprotonated and reforms the carbonyl
- Secondly, this would produce an acidic beta proton that would
want it to be protonated in base causing the second product from a base
catalyzed dehydration of the C1 alcohol
- Propenal (another of the observed products)
- Lastly, the C4 still
has the HO-O with a carbonyl and this would be released as a leaving
group with a nucleophilic addition to the carbonyl
- This releases the OOH in exchange for an OH
- The nucleophilic addition reverses reforming the carbonyl and the OH is deprotonated to produce the last part of the prodcut
- 2)Oxygen independent - alkali-labile lesion via beta-elimination
- Creates 3' phospahte terminus "by complex chemistry that remains to be elucidated"
- In this scheme the (oxygen independent) basic surrounding
attacks the radical initiating an immediate base catalyzed epoxide ring
opening from the C4 position instead of the C1
- The phosphate acts as a good leaving group which is probably SN2
attacked coupled with an acidic proton created with the formation of a
carbonyl
- Lowers the energy of the molecule
- dehydration of the OH probably coupled with the nearbly acidic proton creating water and the observed double bond
LOC:
Treatment:
Palitative Treatment - treats partial but not cure
- Testicular cancer
- Head and neck cancer
- Lypmphoma
Possible Side Effects:
- Hyperpigmentation
- 3n case report
- Developed after being treated for vascular anomalies
- Venous malformation (cheek, cervical, proliferating haemangioma forearm)
- Time of reaction not stated
- ?Electrical link?
- Corresponded to site of ECG electrode placement
- Melanin proliferaion?
- Hyperpigmentation faded after 95-120 days
- Author "We hypothesize removal of
adhesive ECG electrodes potentially resulted in cutaneous blood vessel
microtrauma allwoign bleomycin to diffuse into the skin in higher
concentrations than nomal. Hyperpigmentation may have then developed" -
Really?
- Arterial thrombosis
- Was used after Etoposide, Cisplatin then Bleomycin
- Chemotherapy for testicular cancer
- ?Hormonal effects of blood? - both had orchiectomies, first case didn't use bleomycin
Concepts:
Additional Information:
