You are now an expert in Cell Cycle and DNA Replication and have been called upo

Question

You are now an expert in Cell Cycle and DNA Replication and have been called upon to develop a new cancer drug. A hallmark of cancer is the uncontrollable division of cells and the growth of tumors. Propose a mechanism for anti-cancer drug that would block one of the processes necessary for cell division or DNA replication ultimately blocking the growth of tumors. Explain why you are targeting that particular gene/protein/pathway. Include the normal function of the gene/protein/pathway in your answer.

Explanation / Answer

While making an anti cancer drug, we should keep both the processes in mind, uncontrollable division of cells and the growth of tumors, because either one of them left untreated will increase the chances of cancer. Cell cycle has 5 phases - G0, G1, S, G2 and M.

a) Gap 0 (G0): This is the time when a cell will leave the cycle and quit dividing. This may be a temporary resting period or more permanent.

b) Gap 1 (G1): Cells increase in size in Gap 1, produce RNA and synthesize protein. An important cell cycle control mechanism activated during this period (G1 Checkpoint) ensures that everything is ready for DNA synthesis.

c) S (synthesis) Phase: To produce two similar daughter cells, the complete DNA instructions in the cell must be duplicated. DNA replication occurs during this S phase.

d) Gap 2 (G2): During the gap between DNA synthesis and mitosis, the cell will continue to grow and produce new proteins. At the end of this gap is another control checkpoint to determine if the cell can now proceed to enter M (mitosis) and divide.

e) Mitosis or M Phase: Cell growth and protein production stop at this stage in the cell cycle. All of the cell's energy is focused on the complex and orderly division into two similar daughter cells. Mitosis is much shorter than interphase, lasting perhaps only one to two hours. As in both G1 and G2, there is a Checkpoint in the middle of mitosis that ensures the cell is ready to complete cell division.

Cancer cells reproduce relatively quickly in culture. In the Cancer Cell, CAM compare the length of time these cells spend in interphase to that for mitosis to occur. A disregulation of the cell cycle leads to the formation of tumor. Some genes like the cell cycle inhibitors, RB, p53 etc. When these genes mutate, it may cause the cell to reproduce uncontrollably and results in the formation of tumor. Although the duration of cell cycle in tumor cells is equal to or longer than that of normal cell cycle, the number of cells that are in active cell division in tumors is much higher than that of normal tissue. This results in a net increase in cell number as the number of cells that die by apoptosis or senescence remains the same. As the DNA is relatively exposed during cell division and hence are susceptible to damage by drugs or radiation, the cells which are actively undergoing cell cycle are targeted in cancer therapy. This information is made use of in cancer treatment. This process is known as debulking which includes a significant mass of the tumor to be removed which pushes a significant number of the remaining tumor cells from G0 to G1 phase. After debulking procedure, radiation or chemotherapy kills these cells which have newly entered the cell cycle. The fastest cycling mammalian cells in culture (crypt cells in the intestinal epithelium) have a cycle time as short as 9 to 10 hours. Stem cells in resting mouse skin may have a cycle time of more than 200 hours. Most of this difference is due to the varying length of G1, the most variable phase of the cycle. The cycle time in M and S do not vary much. In general, cells are most radiosensitive in late M and G2 phases and most resistant in late S. The pattern of resistance and sensitivity correlates with the level of sulfhydryl compounds in the cell. Sulfhydryls are natural radioprotectors and tend to be at their highest levels in S and at their lowest near mitosis.

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