Question - Many cancer drugs either damage DNA or are metabolic inhibitors of deoxyribonucleotide metabolism and interfere with, or prevent, DNA replication. Unfortunately, these drugs work indiscriminately and kill not only cancer cells but also kill other rapidly dividing cells in the body. Furthermore, treatment with many of these drugs also may cause mutations in DNA and often predispose patients to other cancers that may occur many years later!

One anticancer drug, Methotrexate, is a potent competitive inhibitor of dihydrofolate reductase (dHFR) and binds dHFR about 1000 times more tightly than dihydrofolate. High dose methotrexate is often used for treatment of breast, head and neck, leukemia, lymphoma, lung, osteosarcoma, and bladder cancers either alone or in combination with other anticancer drugs.

Please answer the following questions:

1. The synthesis of what deoxyribonucleotide will be directly affected by inhibition of dHFR?

2. Explain why Methotrexate treatment of cells can cause misincorporation of uracil into DNA.

3. Even though methotrexate inhibits dihydrofolate reductase it has  broad reaching effects on other metabolic pathways. Explain why  methotrexate would also inhibit purine nucleotide metabolism, methionine  metabolism and potentially interfere with all reactions involving  single carbon carriers in cells.

4. Why do you think low dose Methotrexate treatments are used as immune  system suppressants or for treatment of psoriasis, a skin disease that  typically occurs by the over proliferation of skin cells?