ON NATURAL MEDICINES
Andrew Dodds writes:
"It isn't very surprising that plants contain anti-cancer
chemicals; they have being fighting a biochemical war against the
world's animals for approximately 300 million years (land plants,
anyway..) and have hence evolved chemicals that probably interfere
with virtually every biochemical pathway that exists. Hence it is very
likely that there are chemicals out there that interfere with those
chemical pathways crucial to the survival and proliferation of cancer
However, this does NOT mean that 'natural is
best'. First, the compound in question will only fight cancer as a
secondary effect to it's primary purpose (killing an insect that feeds
on the plant, for instance). Hence a synthetic derivative may be far
[natural] compound may be too unstable in vivo, so
again a synthetic derivatives will be more successful.
dose ranges (between ' no effect' and 'killing the patient') may be
quite narrow, making direct consumption of leaves/bark/etc either
ineffective or highly dangerous or both.
In short, the 'big pharma' versions of these
'natural' drugs are going to be more effective.
That does not mean
that all information from these companies should be taken uncritically
at face value - you should always look closely and critically at the
real data supporting the claims made. However, at least this is
possible. With alternative 'cures', all you get is the
posted by Andrew Dodds to
One reason cancers are challenging to treat is the
molecular processes and mutations within the cells can vary, even
within the same types of lymphoma, sometimes partly nullifying how
well a drug works, even in different patients with the same
Still another challenge of determining safe and
effective drug dosage is related to inherited differences in
patients known as normal genetic variations or genotypes. These
normal individual variations, similar to what determines our eye
color, can affect the clearance rates of drugs.
To deal with these variations (the heterogeneity of the disease and
the patient), a personalized approach to medicine is evolving.
Advanced tests, such as molecular profiling, is
slowly becoming the basis for therapies tailored for individual
patients. Investigators are actively designing and validating
the new tools that are essential realizing this goal. (See
for details NBN)
Accelerating progress also requires adopting common
standards and platforms for sharing data across trials. We need more
coordination and research to account for the variables underlying the
myriad molecular pathways of disease. We may need to protect or
increase incentives to achieve these goals …and more aggressive
leadership in this area.
Preclinical research must be better able to predict active and toxic
agents before the human phase of development as in the FDA's Critical
Path. Studies that incorporate molecular profiling and less toxic
immunotherapies may be more reasonable as treatment decisions to
patients concerned about the risks of new investigational
In addition to answering important clinical questions, studies must be
reasonable as treatment decisions both to the participant and their
physicians - not as an afterthought, but at the outset. This should
hold true for the first line, relapsed and refractory settings.
It seems also that we should give community doctors incentives to
refer patients to trials, perhaps recognition awards could be
Finally, we need to educate about the process
and the importance of participating in credible medical research. We
must address misinformation and wishful thinking about some
alternative practices, which by definition have not been evaluated
For cancer therapy the state of the art is still mainly chemotherapy, which has some degree of specificity ... because most chemo agents are
toxic to dividing cells. Thankfully!, blood cell cancers are typically
highly sensitive to chemo- and radio-therapies. But we need to improve on
The big improvement in recent years has been from antibody therapy: Rituxan
and RIT. Here the specificity is improved: The range of cells affected by
therapy are reduced dramatically to one type: mature b-cells that express
cd20 - normal and malignant. Importantly, immature normal b-cells are not
effected, because they do not have cd20, allowing new mature b-cells to replace those eliminated by treatment.
Anyone trying to get rid of dandelions understands the concept of
specificity. You can spray the entire lawn with chemical - a systemic approach. The chemical sticks mainly on broad leaf plants. But this method
also does harm to the living soil, the ground water, and to beneficial plants and
(For the record, I hand pick them ... highly specific, but
this approach is
unrealistic on a large lawn!)
The way our immune systems works to remove infection and cancers is highly
You get the mumps once, because your immune system recognizes the unique
antigens of the mumps virus. Once eliminated, memory cells remain on guard
and will execute a fast and furious assault on the virus should it ever try
to reenter the premises. It's so efficient that you'll not even know that
the battle occurred.
Both the positive and negative impact of immunity on lymphomas is not fully
understood (not nearly so), but knowledge about it is accelerating, and a
consensus is emerging that immunity against lymphoma plays a significant
part in clinical outcomes ... in how fast or slow the lymphoma progresses;
in spontaneous regressions; and even in the durability of the response to standard therapy.
Progress is accelerating in immunotherapy, because of recent
breakthroughs, such as how to target immune checkpoint
blockade - how cancers cells put the immune Effector cells to sleep,
and because of adoptive t-cell therapy - the development of living
drugs that are designed to target cancer cell molecules on the cell
surface, such as cd19 (CART 19)
We are entering an exciting and
promising era in cancer therapeutics. Our goal is to foster a general understanding of how
agents (standard and targeted) for lymphoma are thought to work - as
an aid to informed consent.
A little History
Our ancestors have used
plants, minerals and animal parts as medicines to relieve pain and
suffering from disease. Today the endeavor continues, aided
by insights into how drugs act against disease, and, of course, a
much better understanding of disease processes, but also the ability
to modify drug compounds in order to better target disease processes
or reduce toxicities.
Still the answers cannot come quickly enough, and
people continue to die and suffer from cancers and other
diseases. The process of drug discovery and testing is not
fast enough, or efficient enough. "The patients are
sidebar on NATURAL MEDICINES.)
The objective here is to answer some basic
questions about drugs:
What is a
What makes a drug
What makes it
How do drugs work?
Terms like: affinity,
specificity, pathway, PK, mechanism of action, synergy ...
Why does it take so
long to develop and test new drugs for cancers?
What is a Drug?
The first question is the easier to answer.
A drug is a compound used (ingested,
infused, or applied) to correct, slow down, or relieve a medical
condition. A definition that could apply to chicken soup for
the common cold, or to Cytoxan for a cancer. For the
first example, the mechanism is lacking and the evidence is thin.
A distinction should be
made between a food and a drug. Foods provide energy and
nutrients to support health and functions. Most drugsmust be absorbed into the blood at sufficient
levels to affect the disease process.
Notably, FDA oversight begins when medical
claims are made for the intervention.
Chicken soup is a food, of
course, but if promoted as a cancer cure, it could then be regulated
as a drug, and the sponsor would have to prove it first before being
able to market it as such.
Is the drug active? Is it effective?
What's the difference?
active drug stops or interrupt a disease process, such as cell
division in cancer. However, an active drug is not necessarily an
effective drug, because the side effects might offset the positive
For example, you might shrink a tumor with a new compound,
but also do greater harm to bone marrow function. That is, an active
drug may not help the patient to live better or longer, even if it's
active against the disease.
An effective drug is one that has been
proven to provide a net benefit: the positive effects exceed
the negative and the patients are better off to use the intervention
than to let the condition run untreated, or treated with another
In other words, an effective drug is one that provides
benefit, and the most convincing measure of clinical benefit is
when the drug improves survival compared to another effective drug. This
assessment is made possible by randomized clinical trials that test
the new drug with the standard of care.
Note: Sometimes surrogate measures of benefit
(surrogate endpoints) are used when it's not feasible to measure
survival, such as comparing time to progression in each arm of
the study comparing two treatments.
So an effective drug provides
clinical benefit, which is best measured by an improvement in
survival, but also if it can stop or reverse a disease process when
no other therapy can. An effective drug might
also provide relief from symptoms, without impairing survival, or
quality of life.
The search for effective drugs starts with agents
that seem active in pre-clinical experiments.
Active drugs interfere with a disease processes.
The mechanisms of action (how they work) are many. It
may be useful to think about drugs that are very familiar to us.
Aspirin, for example, can help
to reduce the sensation of pain by inhibiting inflammatory
enzymes in our body.
Other painkillers put
locks on neural receptors to
reduce the sensation of pain.
Antibiotics, such as the
well-known penicillins, work by killing bacteria.
They do this by interfering with the formation of the cell walls or cell
contents of the bacteria. Other antibiotics work by stopping bacteria from
damage rapidly dividing cells, causing the cells
to self-destruct ... not unlike skin cells do when exposed to
too much sun.
Before aspirin there was willow bark. Opium and
cocaine relieved pain. Early
scientists extracted and purified the active ingredients from such
early natural compounds. Clever organic chemists delighted in fragmenting
these molecules in order to find their structures.
Aspirin and penicillin have been around for a long time, but the
drugs that stop and kill cancer cells are among the newest drugs
being discovered and fine-tuned.
How do scientists develop them?
we know what happens when a drug is received in the body,
by mouth, IV drip, or by patch?
Drug Discovery or Design
investigation is done in phases: preclinical, clinical
(human testing), and regulatory assessment.
The first task in in the preclinical phase is to
find by screening or design a promising compound and then to determine how much of the drug
is needed to do the job. The necessary concentration is determined
in preclinical experiments involving cell cultures as in the
well-known Petrie dish, or with animals.
(NOTE: This phase is essential to credible
drug research. Sometimes herbal products are inappropriately hyped
as cancer treatments based on cell culture experiments, without
accounting for the concentration needed in the blood to achieve
the cell-culture effect, or if that concentration would be toxic.)
Increasingly for cancer and other diseases new compounds are
designed to bind to parts of cell that are driving cell survival or
proliferation. These abnormal working parts of the cell are called
Agents that target disease pathways
In the body the drug interacts with, binds to, or
disrupts, some process underlying the disease. Targets of the
compound can be cell membranes; enzymes, structures or carriers -
all proteins - or any one of the cellular chemicals or processes
that have been hijacked to keep the disease going.
The fit between a drug and a body molecule or
diseased cell structure is known as affinity.
important goal of therapy related to affinity is
... that the compound binds as exclusively as possible to the target of
treatment and minimally impairs normal processes.
The interaction between drug and disease is known
as mechanism of action - how the drug works.
However, even well-targeted drugs, such as the
cancer drug Gleevec, can have off-target effects: significant
side effects, emphasizing
the need for caution in the testing of new drugs in human subjects,
particularly classes of drugs that work by new mechanisms of action
or even when approved agents are combined for the first time.
A relatively new drug target is found on the
of cancer cells. These are molecular binding sites. One
binding site, known
as CD20, is targeted by the drug Rituxan. Here a mouse/man-made
antibody binds to the CD20 receptor which can cause the cell to
self destruct, or leads to killing of the tumor cell by immune cells.
antibody engaging b-cell tumor images
The field of identifying new potential
targets is accelerating. Drug targets may be within
the cell, such proteins or genes that prevent cell death, on
the cell surface as described above, or the target may be other
"normal" cells that contribute to the survival and
expansion of the malignant cells in the tumor microenvironment.
Many chemotherapy drugs exploit the overt behavior
of cancerous cells - rapid cell division. The dividing cell
more readily takes up the drug, which leads to damage of its DNA
(the vital information that determine cell behavior and
functions) which is more vulnerable during cell division. ...
... The cell, detecting the damage to
its DNA , self destructs in a process called apoptosis,
similar to when diminishing light triggers leaves to fall from
Abnormal cells, being living parts of the body, can
adapt to drugs leading to drug resistance. Here getting
the dose right and the rationale combination of drugs can
minimize the ability of the cells to adapt and survive.
Combining drugs can have an ad
There can be an additive or synergistic
effects when combing drugs agents. Also it's possible that one
active agent can work against the mechanism of another active agent
(as an agonist) - such as when the second agent causes cell
cycle arrest, which is needed for first agent to work.
Synergistic: 1+1 equals 3
Agonistic: 1+1 is less than 2
Researches will also study the mechanisms of
resistance. To do this they will need tumor sample from the
participants of studies - samples before and after resistance to
identify what pathways are turned on in the cells that survive the
targeted agent - that may also be targeted. ... As was done with
Identifying the Right Dose: the
The dose differentiates a remedy
and a poison. ~ Paracelsus
That a compound is active is just the
starting point in the drug development process.
might be highly toxic at the concentration needed be active in a
test tube (In vitro). Or it may not be absorbed well if taken
orally, or it may be cleared too quickly to have a meaningful
treatment effect in the body (in vivo).
pharmacokinetics (PK) is an essential part of new drug development and assessment in the
clinical phase. It's the study of what your body does to a
drug. The initial PK research is carried out on animals and then
ever-so-slowly and carefully in humans. See also
How long the drug remains in the bloodstream, and
at what concentration, are vital to the safety and effectiveness of
drug, which are determined by
The organs that have a major impact on ADME are
the liver and the kidneys and therefore
function are monitored very closely when new drugs are first
administered in humans.
differences in ADME can result in faster or slower clearance of
the drug from the body.. Differences in clearance rates can affect
the course of treatment and severity of side effects.
also the side bar on HETEROGENEITY.)
If the drug remains in the blood too long it can increase side
effects. Conversely, a drug that's excreted or cleared too rapidly
will not be around long enough, or at the proper concentration, to
do its job well.
Moreover, interaction with other drugs or herbs can affect how drugs
are absorbed or cleared from the body.
Yet another vital aspect of the drug development and
testing is the called pharmacodynamics, or PD, which
is the study of the effects of drugs on the body or on disease processes
within the body and the mechanisms of drug action and the relationship between drug concentration and effect.
The objective of PD studies is to identify the
window: the dose needed to achieve sufficient levels of
the agent in the blood at acceptable toxicity.
The larger the therapeutic window the more likely the drug can
be administered in a safe and effective protocol.
If the new drugs shows reasonable safety
and activity in early phases of clinical trials, it is then tested
against approved therapies in large randomized controlled clinical
trials. The goal of phase III studies is to objectively
determine the safety and efficacy in a way that minimizes bias.
Notably, failures outnumber successes in the drug
development process. Only 1 in 5,000 new compounds evaluated in the
preclinical stage makes it to the clinic ... and about 1 in 5 new
therapies that reach phase III clinical testing.
The regulatory evaluation of the
data submitted by the sponsor for marketing approval does not take very long ... about 6
to 9 months; while the
preclinical and clinical testing phase can take ten years or longer.
The cost to the sponsor can exceed 1 billion dollars.
Because the financial risks of
cancer drug development are high and most new drugs fail to win
approval, incentives (primarily in the form of marketing
exclusivity) are granted to new drugs that win approval.
Introduction to Pharmacokinetics