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1. Introduction
2. Outline of talk
3. Mitomycin properties
4. Mode of action
5. Mitomycin C is inactive in its quinone form
6. Basis of the reductive activation of mitomycins
7. The mitomycin "reductive activation cascade"
8. Leuco-aziridinomitosene may decay by reoxidation
9. O2 inhibits the first step of reductive activation
10. Concept of bioreductive anticancer drugs: Sartorelli
11. Reaction products of mitomycins with DNA
12. Isolation of reaction products of mitomycin C
13. Isolation of a fourth adduct
14. Structures of the adducts
15. Sequence recognition in the first alkylation step
16. Mechanism of the CG*CG recognition selectivity
17. Proof of the proposed minor groove alignment
18. Molecular recognition of DNA sequence
19. CpG or GpC cross-links?
20. Orientation of the intermediate monoadduct
21. Molecular evolution
22. Mitomycin C selectively recognizes 5-methyl CpG
23. Why does MC alkylate preferentially guanines?
24. 5-fluoro-C substitution has opposite effect
25. Further evidence of the hypothesis
26. Significance of special recognition of 5-methyl C*G
27. DNA adducts formed in vivo
28. Major metabolic fate of MC: reduction to 2,7-DAM
29. 2,7-DAM adducts in MC- & 2,7-DAM-treated cells
30. Models of minor and major groove monoadducts
31. Biological activity of 2,7-DAM and its DNA adducts
32. Large array of different adducts
33. Structure-function relationships of DNA adducts
34. Individual adducts selective introduction in the cell
35. The dG-2,7-DAM 5 adduct is not mutagenic
36. Neither adduct 1a nor adduct 5 is mutagenic
37. What is the basis for the different cytotoxicities?
38. Differential blockage of replication?
39. MC monoadduct blocks Klenow DNA polymerase
40. T-7 exo- polymerase by-passes 2,7-DAM
41. MC monoadduct blocks T-7 exo- DNA polymerase
42. Single nucleotide incorporation
43. Conclusions from in vitro primer extension study
44. Other studies of mitomycins in our laboratory
45. References

Topics Covered

• The mitomycins: structures, properties, early research of the molecular basis of biological activity
• Reductive activation
• Chemistry of the interactions with DNA: DNA adducts, cross-linking of DNA
• Molecular recognition of DNA
• Metabolic chemistry
• Structure/activity relationships of the DNA adducts

Links

Series:

• Chemical Biology

Categories:

• Biochemistry
• Cancer
• Cell Biology

Therapeutic Areas:

• Oncology

Talk Citation

Publication History

• Published on August 14, 2008

Financial Disclosures

• Prof. Maria Tomasz has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.