Re: How does Taxol, Lapachone "fix" bad checkpoints?

From: Robert J. Bradbury (
Date: Sun Jul 16 2000 - 07:51:17 MDT

On Sun, 16 Jul 2000, CYMM wrote:

> I know that beta-lapachone is a topoisomerase inhibitor; as is curcumin
> (from turmeric) which also displays similar antitumour activity. And Curcuma
> plants & Lapacho (pau d'arco) trees are a dime a dozen where I live.
> Could anyone explain why this should effectively "fix" checkpoints?

I haven't researched this stuff in years, but my impression would be
that anything that slows down the cell cycle (such as a topisomerase
inhibitor) should help. (Topisomerases function to relax supercoiled
DNA, which is what you get when you unwind DNA for replication).

You have to keep in mind that the checkpoints for DNA replication
and repair (for 3 billion bases) really must be a *kludge* of
a system. To replicate 3 billion bases in perhaps 8 hours
(1/3 of a cell cycle?), with an enzyme (DNA polymerase) that
can copy perhaps 30 bases/second requires ~3500 copies of
the enzyme running simultaneously. Now add to that the
problem that the copying complexes will variously run into
damaged DNA that has to be repaired (so you have to wait for
the repair complexes to diffuse over to your location...).

I've never seen a way for those complexes to collectively
"vote" to inform the cell "I'm done" in a reliable fashion.
If that is true, then nature must simply have timed the cell
cycle with a fairly conservative estimate of how long the
repair and replication *should* take. If it underestimates
that time -- "ooops". So a decent strategy for preventing
cancer would be to hit cells with substances that don't
*really* damage DNA but activate DNA damage & repair responses
(I don't know what those might be other than thymine dimers),
and also slow down the cell cycle with drugs such as topisomerase
inhibitors. That is going to increase the probability that
all of the DNA is repaired and replicated properly before
cell division is allowed to proceed.

> Remember if you lick atherosclerosis and cancer - you add years to your
> life. If you fix checkpoints a lot of senecent cells also get zapped and are
> weeded out from your body.

If you fix heart disease and cancer, I think you extend average longevity
by ~8-12 years. (See papers on the Compression of Morbidity by J. Fries
from Stanford,

Fixing checkpoints will not zap senescent cells. This involves a
misunderstanding of the purpose of checkpoints and the mechanisms
of scenescence.

The checkpoints exist to regulate the cell cycle so that things
get done in the correct sequence to allow cell division to work.
Scenescent cells are those who have replicated so much that they
have reached the end of the useful reliably "healthy" lifespan.
They presumably have short telomeres. Scenescent cells are
presumably dangerous if they continue replicating (usually
having turned on telomerase to achieve this).

So, to block the replication of cells have escaped from the
scenescence path (potentially having accumulated lots of DNA
mutations due to their lengthy replication history) you need drugs
like telomerase inhibitors or topisomerase inhibitors. To *kill*
them you need to activate the apoptosis pathway (if it still
works) with some nasty toxins or a lot of DNA double strand
breaks (e.g. radiation). Scenescent cells, that stay scenescent,
are probably not very dangerous or harmful (over time they probably
function less and less efficiently). Its the cells that have
bypassed the scenescence blocks that have the potential to
cause cancer. Where some confusion creeps into this is due
to the fact that the p53 gene is a major player in both the
"damage is present, lets slow down the cell cycle" pathway and
"really bad damage is present, lets commit Hari Kari" pathway.

It is worth noting that to fix both heart disease *and* cancer
you have a sticky problem. You want to add telomerase inhibitors
to block potential cancers in the body but you want to add
telomerase promoters to extend the replacement capacity of
scenescent cells at the high-pressure (= high wear & tear)
locations in your arteries. Telomerase promoters would probably
also boost the decline in your immune system with age.

So solving these problems simultaneously is not going to be easy.


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