6) Case Study: Cancer Drugs DNA-damaging agents have a long history of use in ca

Question

6) Case Study: Cancer Drugs

DNA-damaging agents have a long history of use in cancer chemotherapy. The full extent of their cellular mechanisms, which is essential to balance efficacy and toxicity, is often unclear. In addition, the use of many anticancer drugs is limited by dose-limiting toxicities as well as the development of drug resistance. Novel anticancer compounds are continually being developed in the hopes of addressing these limitations; however, it is essential to be able to evaluate these compounds for their mechanisms of action.

a. One example of a DNA-damaging agent that interferes with DNA synthesis is aphidicolin. Knowing that it interferes with DNA synthesis, propose three hypotheses of how this agent might accomplish this (think about potential targets and mechanisms you have learned about in the cell).

b. Another set of DNA-damaging agents are alkylating agents, which either cross-link (create covalent bonds) between DNA and proteins or between DNA bases on the same or opposite strands. Hypothesize how these agents might specifically interfere with replication. Offer three different potential modes of action.

c. Clearly DNA replication is important for almost all the healthy cells in our body. How do these DNA-damaging agents manage not to kill the patient?

Explanation / Answer

A) Aphidicolin is a drug used as anticancer agent. The drug blocks the DNA synthesis by one of the following ways:

i) Chain Elongation Inhibitors - The drug get phosphorylated by the system kinases and gets incorporated into newly synthesising DNA strand at the 3'OH end. Binding of the triphosphate drug, prevents further adding up of new nucleotides to the DNA strand and thus, short fragments of DNA strands are formed. This action prevents DNA elongation and thus DNA replication is inhibited.

ii) DNA Polymerase Inhibitors - The active site of DNA polymerase binds with dNTPs so that it adds up nucleotides for DNA synthesis. Binding of inhibitors to the active of this enzyme, blocks the dNTPs binding to the enzyme and thus prevents the adding of nucleotides by DNA polymerase to the newly synthesised stand is inhibited.

iii) DNA Topoisomerase Inhibitors - DNA Topoisomerase prevents the DNA strand getting strained during replication. Inhibiting topoismerase enzyme fails to relieve the strains in the DNA strand and thus, DNA strand breaks into fragments and DNA synthesis is incomplete.

B) Alkylating agents is the commonly used for anticancer theraphy. It acts by binding with the DNA bases or DNA protein.

i) Monofunctional methylating agent: This agent will incorporate the methylation to N or O atoms of the DNA strands. Incorporation of methyl group to the bases in the DNA strand, allows it to lose its stability and the DNA is broken into fragments. Thus, replication is prevented.

ii) Bifunctional alkylating agent : These agents interact within the DNA strand i.e., intra crossing
(linking of bases on the same strand) of the DNA strand (for example, one guanine group with other guainine group). This interlinking, prevents the DNA from getting unwind for DNA replication.

iii) Choloroethylating agent: This action is similar to that of the bifunctional alkylating agent, but, in htis case the cross-linking is within interstrand ( linking of bases from one strand with the base on the opposite strand of the DNA). This prevents the DNA undergoing replication.

C) Most of the cell undergo cell cycle in order to undergo cell division. Blocking of DNA occurs at the S-phase of the cell cycle. Anticancer drugs usually targets cells that undergo cell cycle at high rate. Hence, there is increase in the hair fall for patients who undergo chemostherapy(hair cells divides fast). Thus, there is a less possibility of the drug to affect the normal cell cycle in the system.

Moreover, in tumor cells repair mechanism fails but it is active in normal cells. Thus, the DNA damage to the normal cell undergo repair mechanism.

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