Attacking Cancer - Fighting with Filaments
Overview
By targeting cytoskeletal filaments such as actin filaments and microtubules, scientists hope to attack cancer cells by disrupting their ability to divide, grow and maintain normal function. Anti-cancer drugs such as taxol and colchicine prevent cancer cells from entering mitosis by greatly stabilizing microtubule structure and thus inhibiting the formation of the mitotic spindle. These drugs can also disrupt the mitotic spindle during the metaphase/anaphase of the cell cycle by destroying microtubule structures, leading the cell into apoptosis. Furthermore, antimitotic compounds such as discodermolide and epothilone can be used to stop the development and proliferation by inhibiting the polymerization of tubulin. Though these treatments are effective, current anti-cancer drugs suffer from specificity; they cannot differentiate between normal and cancerous tissue and therefore cause damage to both.
Therefore, researchers are concerned with finding ways to differentiate between cancer and normal cell dynamics. For example, there are 12 different tubulin isotypes that exist at varying degrees in certain cell types and that also have distinct responses to certain drugs. By finding more information about the differentiation of different cell-types (in this case normal vs. tumor cells), scientists can better develop drugs that target specific isotypes and thus only attack cancerous cells without damaging normal human tissue. Since the actin cytoskeleton is greatly modified in tumor cells due to their abnormal growth and increased ability to divide, scientists have used proteins such as gelsolin and cytochalsin B which have been shown to affect cancerous cells more so than healthy cells. Many actin-targeting compounds are derived from natural marine products such as the lantrunculins.
Why?
Dr. Eschenbach, the Director of the National Cancer Institute stated in September 2004, “…the painful reality is that as we sit here today, one American every minute continues to die from this disease. It remains the disease that Americans fear most because of the suffering and devastation as well as death it brings, and we know that one out of every two men, and one out of every three women in their lifetime will be told they have cancer.” Although many advances in the treatment of cancer have been made such as chemotherapy and radiotherapy, current treatments are extremely painful and have terrible side effects. Chemotherapeutic drugs are cytotoxic drugs that attack cells that are dividing in the body. These drugs are released into the body and damage cancer cells that are dividing uncontrollably anywhere in the body. Since most cells are mature and have stopped dividing they are not susceptible to these effects. Unfortunately healthy cells that are constantly dividing can be damaged as well thus leading to common side effects such as hair loss, lowered blood count and nerve damage. These complications could be reduced and even eliminated with the advancement of specific or localized drug delivery research.
6 comments:
Ryan: the topic is very interesting and relevant, especially reaffirms why understanding of cytoskeleton (which often seems to be looked down upon) is so crucial in molecular biology as well as bioengineering. Could you actually post the link to the paper you are referring to? I'd be very interested in reading the paper. Also, you mentioned that scientists have used certain proteins to attack cancerous cells since actin cytoskeleton is greatly modified in tumor cells. Do you happen to know what modifications these actin filaments specifically depict in cancer cells?
I can't really see how this method is any better than the other relatively non-specific targeting mechanisms out there. That one part from the paper: "Important unsolved questions concerning the antitumor
activity of microtubule-targeted drugs are, firstly, the basis
of their tissue and tumor specificity..." makes me wonder how specific this method can actually be? Have they done any kind of in vivo testing with their proposed drugs? I could imagine that there isn't one specific isotype of microtubule that only exists in transformed cells. What's the non-specific damage going to be like?
Interesting paper. You said that the tubulin structure of cancer cells is greatly modified - how so? Is it stronger, larger, more elastic or what? Also, are there cancer drugs like this one out on the market for human use or is this only laboratory research now?
Ryan, you bring up a fascinating topic about the treatment against cancer. I’m wondering about the machinery in which the actin subunits are inhibited by these drugs, namely if they are both the same in both cancerous and non-cancerous forms of actin. This is important because you mentioned that although gelsolin and cytochalsin B are effective against the cancerous form, there is some affinity with the regular actin units as well. Getting back to my original question, is the partial affinity due to a similar mechanism of inhibition?
At least from what I understand, actin filaments in transformed cells are much more unstable than non-tranformed cells. Actin grows in a unidirectional pattern in which the front end is extended while the back end is being simultaneously degraded in order to provide more subunits for the forward growth. I suppose that the instability of the actin could occur somewhere during this process. For example, we know that transformed cells grow and migrate at a higher rate than normal. This higher frequency of development may not allow the processes in which actin is extended to stabilize the structure. In this way, we could try to use different concentrations of certain drugs or even mixtures of various drugs in order to find a point in which it will be able to disrupt the instable actin in transformed cells but not normal cells.
The paper says that cancer cells have their filaments structures different from that of normal cells, and some drugs can detect this difference and target specifically on cancer cells. I am wondering how do the drugs detect the cells that have different filament structures from the normal cells. Do the cancer cells have some special ligands on their surfaces, so the drug will target on them??
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