Thursday, April 2, 2009
Cancer
On pages 182-185 it talks about evolution in nature that causes mutations like cancer. How is cancer formed and what is metastasis and how does it connect to evolution? Include some of the drugs that treat cancer, and give a specific example from the book and discuss how the drug works. In your discussion talk about the resistance patients evolve to these drugs and what can be done to limit the resistance. You may want to include some of the biological themes like evolution and emergent properties and talk about how the current research will lead to future medicines and therapy dealing with cancer.
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Cancer is created by the formation of a tumor, which is created by “chance mutations, selection, and time” . . . through “mutations that compromise the mechanisms that control how cells multiply and how they interact with their neighbors” (Carroll 182). Some mutations allow cells to proliferate in parts of the body unchecked. A metastasis is when “additional mutations occur that may give cells the ability to leave their original location and travel to, invade, and proliferate in other body tissues” (183), as defined by Carroll. Evolution in a species happens due to certain mutations; genetic recombination allows certain species to adapt due to changing environmental conditions or otherwise. The most advantageous mutations are then eventually picked by natural selection as allowing the species to be at its “fittest”. Mutations, however, are random, and thus, cancer is a disadvantageous mutation.
ReplyDeleteBiologists have expanded their knowledge of the “genetic and molecular mechanisms of cancer formation” (Carroll 183). They identified specific genes that mutate in particular cancers; chromosomes can break and attach genes to one another, disrupting the regulatory protein called ABL kinase, then predisposing cells to become cancerous. The Philadelphia chromosome is associated with chronic myelogenous leukemia (CML in short).
A drug was eventually made to treat CML; it was called Gleevac/Imatinib. The discovery of particular altered genes in cancers allowed new therapies to be tried instead of destroying all rapidly dividing cells, healthy or otherwise; in other words, “rational chemotherapeutic drugs” were used, Gleevac being a specific example. Gleevac efficiently targeted the ABL kinase in CML tumors; it functions by latching onto a particular part of the ABL kinase protein and thus, inhibits its activity.
However, eventually, CML developed resistance to Gleevac, due in part to the fact that Gleevac is a toxin to CML cells; selection of certain mutations have naturally selected the genetic material of CML cells that would allow it to resist Gleevac the most efficiently. The mutations that were found in CML cells were observed to have developed on the ABL kinase gene, the same mutation occurred in patients that had Gleevac resistant CML. The mutation “causes the replacement of a threonine in the ABL protein with an isoleucine” and changes the shape of the “pocket” on the ABL kinase that Gleevac latches onto normally.
Resistance happens in all specific drugs that treat different cancers. For example, Chronic Eosinophilic Leukemia (CEL) is specifically treated with Glivec. As can be predicted, extended use of Glivec can lead to “resistance to Glivec, rendering this chronic form of leukemia untreatable” (source: http://www.medicalnewstoday.com/articles/43260.php). Sorafenib/Nexavar was then developed to treat patients that have developed the resistance to Glivec. A combination of specific drugs may be helpful in treating specific types of leukemia and cancer.
Charles Sawyers and his colleagues are also working on an alternative drug to Gleevac, another ABL kinase inhibitor called BMS-354835. Like patients’ post-resistance to Glivec, this is an alternative drug to use after patients have developed a resistance to Gleevac. This is an artificial way to keep up with cancers such as CML after they have selectively adapted and became resistant to current treatments. In both cases of CEL and CML, combination therapy is a possible strategy in dealing with cancer. Understanding “mutation, selection , and evolution” (Carroll 184) can help create new ways to treat cancer. Mutation is random and thus, when studies showed that CML patients had Gleevac-resistant mutations before treatment, it was significant. A sub-population of cancer cells will possibly randomly mutate and be resistant to a drug. This population will survive the treatment and then proliferate. Combination therapy is using two different drugs to eliminate CML cancers before resistance evolves in cancer cells; it is to stop evolution in its tracks before the cancer becomes uncontrollable. As seen by CEL treatment, the way CML is treated is being spread to other cancers in order to create a higher recovery rate among cancer patients.
As said in the other comment, Carroll says that a tumor develops from “chance mutations, selection, and time” that are the three major parts of evolution (182). Out of the trillion cells that make up our bodies, many cells are always being replenished. This allows many potential situations for mutations to occur and this is how cancerous tumors start.
ReplyDeleteOne of the main causes of a malignant tumor is a mutation in the cell cycle. A normal cell replicates so many times until it hits a point in its cycle that tells it to stop and it performs the programmed cell death. A cancerous cell, however, bypasses this step in the cycle and just keeps replicating. It doesn’t perform the programmed cell death and therefore spreads its infections to new cells at an alarming rate.
Mestastasis is the spread of a disease from one organ to a non-adjacent organ. This occurs with malignant tumor cells and infections. Cancer cells often spread from their primary source into blood vessels and circulate through the bloodstream. Then, it can affect other areas of the body.
Evolution wise, the mutations that occur in cancerous cells are not to the advantage of the organism. Therefore, not being a selective advantage, they are often not as easily passed on through genes. However, the large number of cells that they infect show a significant impact on the body and are sometimes passed down to offspring.
Medically, cancer is often treated with biological therapies (interferon and interleukin) to strengthen the immune system, chemotherapy, or monoclonal antibodies (Herceptin and Rituxan). Chemotherapy may cause severe reactions such as allergic or hypersensitivity reactions. These trigger an immune system response.
Sometimes, cancer cells become resistant to chemotherapy and may continue to grow after once being responsive to the treatments. If this is the case, it is very possible that the cancer cells that were not initially killed by the chemotherapy changed or mutated to become resistant. These cells then multiply until there are more resistant cells than there are cells susceptible to chemotherapy.
Another way cancer cells may become resistant is gene amplification. Since cancer cells multiply and spread so quickly, there is an overload of genes. A cancer cell may overproduce protein which may cause the anticancer drugs ineffective. Also, cancer cells cam pump the drug out of the cell using p-glycoprotein to get rid of the drug fast enough to survive.
Cancer can be treated by surgery, chemotherapy, radiation therapy, immunotherapy, monoclonal antibody therapy or other methods. The choice of therapy depends upon the location and grade of the tumor and the stage of the disease, as well as the general state of the patient. A number of experimental cancer treatments are also under development. Complete removal of the cancer without damage to the rest of the body is the goal of treatment. Sometimes this can be accomplished by surgery, but the propensity of cancers to invade adjacent tissue or to spread to distant sites by microscopic metastasis often limits its effectiveness. The effectiveness of chemotherapy is often limited by toxicity to other tissues in the body. Radiation can also cause damage to normal tissue.
ReplyDeleteIn theory, non-hematological cancers can be cured if entirely removed by surgery, but this is not always possible. When the cancer has metastasized to other sites in the body prior to surgery, complete surgical excision is usually impossible. Examples of surgical procedures for cancer include mastectomy for breast cancer and prostatectomy for prostate cancer. The goal of the surgery can be either the removal of only the tumor, or the entire organ. A single cancer cell is invisible to the naked eye but can regrow into a new tumor, a process called recurrence. For this reason, the pathologist will examine the surgical specimen to determine if a margin of healthy tissue is present, thus decreasing the chance that microscopic cancer cells are left in the patient.
Radiation therapy is the use of ionizing radiation to kill cancer cells and shrink tumors. Radiation therapy can be administered externally via external beam radiotherapy or internally via brachytherapy. The effects of radiation therapy are localized and confined to the region being treated. Radiation therapy injures or destroys cells in the area being treated by damaging their genetic material, making it impossible for these cells to continue to grow and divide. Although radiation damages both cancer cells and normal cells, most normal cells can recover from the effects of radiation and function properly. The goal of radiation therapy is to damage as many cancer cells as possible, while limiting harm to nearby healthy tissue. Hence, it is given in many fractions, allowing healthy tissue to recover between fractions. Radiation therapy may be used to treat almost every type of solid tumor, including cancers of the brain, breast, cervix, larynx, lung, pancreas, prostate, skin, stomach, uterus, or soft tissue sarcomas. Radiation is also used to treat leukemia and lymphoma. Radiation dose to each site depends on a number of factors, including the radiosensitivity of each cancer type and whether there are tissues and organs nearby that may be damaged by radiation. Thus, as with every form of treatment, radiation therapy is not without its side effects.
Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. In current usage, the term "chemotherapy" usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy. Chemotherapy drugs interfere with cell division in various possible ways, e.g. with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific to cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can. Hence, chemotherapy has the potential to harm healthy tissue, especially those tissues that have a high replacement rate. These cells usually repair themselves after chemotherapy. Because some drugs work better together than alone, two or more drugs are often given at the same time. This is called "combination chemotherapy"; most chemotherapy regimens are given in a combination.
Targeted therapy, which first became available in the late 1990s, has had a significant impact in the treatment of some types of cancer, and is currently a very active research area. This constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, over expressed or otherwise critical proteins within the cancer cell. Prominent examples are the tyrosine kinase inhibitors imatinib and gefitinib. Targeted therapy can also involve small peptides as "homing devices" which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclide’s which are attached to these peptides eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. Especially oligo- or multimers of these binding motifs are of great interest, since this can lead to enhanced tumor specificity and avidity.
Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumors include intravesical BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients. Vaccines to generate specific immune responses are the subject of intensive research for a number of tumors, notably malignant melanoma and renal cell carcinoma. Sipuleucel-T is a vaccine-like strategy in late clinical trials for prostate cancer in which dendritic cells from the patient are loaded with prostatic acid phosphatase peptides to induce a specific immune response against prostate-derived cells.
http://www.cancer.org/docroot/home/index.asp
http://www.cancer.gov/
http://www.webmd.com/cancer/
cancer.about.com/
www.nlm.nih.gov/medlineplus/cancer.html