Topoisomerase inhibitors comprise important cancer drugs e.g. etoposide that targets human type IIA topoisomerases (Top2α and Top2β) causing errors in DNA synthesis leading to the destruction of cancer cells. As such, by trapping the cleavage complexes of the type IIA topoisomerases, etoposide effectively blocks DNA re-ligation, thereby causing DNA strand breaks that, in turn, disrupt the entire process of cell replication and preferentially promote the apoptotic destruction of cancer cells. How does it avoid destruction of the normal cells as that would impact the patient health negatively?
Dear Dr. Utkarsh Ghate
Chemotherapy (including topoisomerase inhibitors) not only kills fast-growing cancer cells, but also kills or slows the growth of healthy cells that grow and divide quickly. For instance, cells that line the mouth and intestine and those that cause hair to grow. Etoposide is relatively cell cycle specific, and it affects cells in the S and G2 phases of cell division. The growth of normal body cells may also be affected by etoposide. However, it is a relatively well-tolerated chemotherapeutic agent. The dose-limiting side effect of etoposide is myelosuppression with neutropenia the principal form of hematologic toxicity. Mild thrombocytopenia, mucositis, nausea, alopecia, and emesis are common. Some effects of the drug may not occur until months or years after the medicine is used.
One may focus on selective protection of normal cells from chemotherapy which would help increase the therapeutic window thereby improving the therapeutic outcome. One may design multi-drug combinations that could be antagonistic in normal cells and synergistic in cancer cells. For instance, one could use ‘two-drug' strategy, wherein the first drug is ineffective against a target drug-resistant cell. Additionally, it must be cytostatic but not cytotoxic. The second drug, which is applied in sequence, must be a cycle-dependent apoptotic drug to which the target cell is not cross-resistant. In this way, drug resistant cells can be selectively killed by a combination of drugs not killing sensitive cells. The lack of toxicity against normal cells will be clinically translated in reduction of adverse side-effects.
More information on using this type of approach may be obtained from the article attached below.
Article Drug-resistance enables selective killing of resistant leuke...
As an example, you may refer to figure 1 in the below attached paper depicting the killing of Dox-resistance cells and sparing the parental cells.
Article Selective protection of normal cells from chemotherapy, whil...
Regards,
Malcolm Nobre
Thanks Malcolm Nobre for the quick, detailed & pertinent reply. A relevant point is that normal cells have higher rejuvenation rate so can recoup soon while cancer cells cannot against chemotherapy drug. Your 2 drug theory is interesting and explains the adjuvant concept to ensure remission
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