Biology 466 Unsolved Problems Fall 2011
Specificity of cancer chemotherapy: Albert Harris, September 22, 2011
LOTS OF CLASS DISCUSSION NEEDED ABOUT THESE TOPICS
You need some reason why a given drug (etc.) will hurt cancer cells more than it hurts normal cells.
This reason might result from faster or less-controlled growth, but might be entirely unrelated to growth.
MORE CLASS DISCUSSION NEEDED #1
Any inhibitor of either DNA synthesis or mitosis gets tried as a cancer treatment, even when there isn't any known reason to expect specificity. For some treatments, specificity often does occur, mostly for unknown reasons.
TIME FOR SOME MORE CLASS DISCUSSION #2
The original idea was that cyclophosphamide would be specific for liver cancers because enzymes found only there cleave cyclophosphamide from an inactive to a reactive form (that cross-links guanine in DNA strands).
Unexpectedly, it works just as well for cancers of many other tissues, but no more specifically than nitrogen "mustard" chemicals that don't need to be activated by enzymes. Specificity without any known reason!
THE CLASS WANTS TO KNOW YOUR THOUGHTS ABOUT THIS. #3
One idea is that damaging DNA produced "unbalanced growth".
A better idea is that normal cells use their checkpoint controls to halt DNA synthesis until repair is finished,
and that cancer cells can't protect themselves in this way, because their checkpoints don't work. (or do they?)
WHAT ARE YOUR THOUGHTS ABOUT THIS? #4
Although embryologists had been studying programmed cell death for a century (frog tail resorption, spaces between toes, death of many specific cells in nematode embryos, etc.) it wasn't realized that one key mechanism is used by all these cases (and that it IS NOT lysosomes). A caspase enzyme was discovered in C. elegans, by a screen for mutations that cause apoptosis not to occur. Many similar enzymes were then found in nearly all human cells, and also proteins for stimulating (fas) & inhibiting (bcl-2) derepression of apoptosis & mitochondrial rupture.
PLEASE TELL THE CLASS WHATEVER IDEAS YOU HAVE ABOUT THIS. #5
Killing of cancer cells by chemotherapy and radiation is now assumed by many to be apoptosis, not necrosis.
(Some have proposed this is also true of cell deaths in heart attacks and strokes; but proof is lacking.)
YOUR IDEAS ON THIS SUBJECT ARE NEEDED #6
Suppose you could invent a drug that selectively prevents apoptosis in normal cells, but not in cancer cells!
Do you see this could turn cyclophosphamide, radiation, etc. into real 100% cures.
I ESPECIALLY WANT TO KNOW WHAT YOU THINK ABOUT THIS POSSIBILITY #7
The G1-S check point control mechanism is strongly believed to be able to shunt irreparably damaged cells
toward apoptosis. Therefore please imagine inventing a treatment that makes cancer cells "seem" (to the check point damage detection system, however it works!) more badly damaged than normal cells "seem".
(For the same amounts of real damage, that is.)
YOUR IDEAS ABOUT THIS, PLEASE #8
Imagine a method that inactivates check point controls in cancer cells, but not (or less) in normal cells.
Note the paradox of basing cancer cures either on decreasing, or increasing cancer cells check point sensitivity.
YOUR IDEAS, PLEASE. # 9
What does it mean if combinations of several different anti-cancer drugs are more effective when combined,
As compared with the effect of larger amounts of any one of the same drugs? Does this imply heterogeneity among the cancer cells? "Maxing out" of effectiveness of any one drug? Multiplicative effects?
OR WHAT? #10