Discussion: Cancer Drugs Target DNA Replication

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.

Post an answer to each of the following questions (300 words max.). You will be able to see your classmates' posts only after you post your own contribution. Also reply to one of your classmates so as to further the discussion: your response can be short but needs to be thoughtful. You may bring in your personal experience or expertise, add a resource or reference, and/or argue with your classmate's reasoning. "Nice job," "Good Answer," or "I agree with you" and any variations thereof are NOT good responses.

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?

Discussion: Evolution of Influenza by Mutation and Recombination

Vaccines are generated against new strains of the Influenza virus almost every year to prevent widespread flu epidemics. This is because the virus can evolve to change some of the proteins in the virus coat to evade human immune systems. In order to create new vaccines for upcoming flu seasons, scientists forecast, or predict, which mutant virus strains will come to prevail and cause possible flu epidemics. This is not a perfect approach because occasionally their predictions will be not quite right and a vaccine will be produced that is only partially active.

The flu virus actually has two mechanisms for evolution: a slow mechanism called antigenic drift and a rapid mechanism called antigenic shift. The slow antigenic drift mechanism is due to minor genetic changes resulting in amino acid changes in two particular coat proteins whereas antigenic shift is due to reassortment of entire regions of the Influenza virus genome leading to exchange of entire genes, or sets of genes, between related viruses.

You can read more about on the Influenza virus in this World Health Organization's short article: Biologicals.

The Influenza virus is divided into several categories, type A, type B, type C and so on. Type A is the major virus type responsible for infection in humans and for infection in several other organisms including pigs and birds. This is a major worry for physicians and scientists because Influenza strains that originally evolved in birds or pigs occasionally undergo antigenic shift and transfer some information from the bird or pig strain to type A strains more likely to infect humans. Antigenic shift is believed to be the mechanism that created strains of Influenza virus responsible for the famous "Spanish" flu pandemic (1918-1920), the "Asian" flu pandemic (1956-1958), the "Hong Kong" flu pandemic (1968-1969), and the "Swine" flu pandemic (2009). Hundreds of thousands to tens of millions people died in each those pandemics, depending on the strain of Influenza virus.

The Influenza virus is a RNA virus and replicates its RNA genome by making RNA copies using a RNA-dependent-RNA-polymerase. Unlike DNA polymerase, the RNA-dependent-RNA-polymerase encoded by the Influenza virus genome has no 3´-to-5´ or 5´-to-3´ exonuclease activity. Since type A Influenza viruses can infect birds, pigs, and humans, it is possible that two type A subtypes could simultaneously infect a single organism. For example, it is possible for pigs to be infected with type A influenza viruses that originated from birds and from humans at the same time.

Post an answer to each of the following questions (300 words max.). You will be able to see your classmates' posts only after you post your own contribution. Also reply to one of your classmates so as to further the discussion: your response can be short but needs to be thoughtful. You may bring in your personal experience or expertise, add a resource or reference, and/or argue with your classmate's reasoning. "Nice job," "Good Answer," or "I agree with you" and any variations thereof are NOT good responses.

1. Create a hypothesis that would explain the mechanism for Influenza virus antigenic drift. Please be detailed and explain why antigenic drift results in amino acid changes rather than reassortment of the viral genome.

2. The rapid evolution of type A influenza virus by antigenic shift has serious implications for the human population. For example, the type A Influenza virus strain H5N1, sometimes found in domestic poultry, rarely infects humans but when infected, Avian H5N1 kills about 60% of the infected humans.

3. Create a hypothesis that would mechanistically explain antigenic shift and how antigenic shift could possibly create a "hybrid" H5N1 Influenza virus that would be highly infectious, and highly lethal, for humans.