The fact that Rajaram explained about various components of a crude formulation triggering more than one pathway is legitimate. And also what Heidi mentioned about the noble prize question of synergistic activity (LOL!) is quite true. Its vast .....very vast and complex to draw down the complete web of action in a cell. like as Heidi you meant that a drug no matter how good it is if not able to penetrate the cell membrane loses its overall efficacy; though with the help of a fellow compound (in the formulation) which may help it get through by increasing its solubility or, manipulating the pH, etc. It is only going to help when we pen down these fragmented thoughts of ours together on a single sheet.

Now again take the example of the traditional medicinal practices like "Ayurveda" etc., where the practitioners (that time) never provided one single plant or derivative as a medicine but they rather made complex formulations involving dozens of plants, which probably complied with their beliefs of theory of Synergism which all four of us mentioned. I adore and wonder how hundreds of years back these guys were sure what herb works where n how, without a western blot PVDF or a Real time!

Ross Cagan (Mount Sinai Hospital), uses drosophila to make cancer "cocktails" of drugs. And he uses MUCH lower concentrations. This is because if you hit one pathway hard, you can be too toxic, so sometime more "pure" compounds don't work as well (or too well toxic to host). Then cancer cells use another pathway or usually many others... so even small adjustments to rates and functioning of various pathways, can help or hinder a growing cancer. Hence your herbs or plant extract hold a "cocktail" of products that the plant has evolved in response to virus, fungus, etc... and it wouldn't have the "extras" unless needed (or a by-product of a needed compound). As Del Wiens use to say, plants only defense is to be extremely good biochemical factories, since they can "run away".

Dear Abhishek Das

I agree with the comment of Heidi Fain. We got the same experience. Crude extracts contain more phytochemicals, which act on a different pathway of cancer cells.I did docking between the phytochemicals of the selected plant vs various targets of cancer. Few drugs act on one target and the rest of things on another target. So each group of phytochemicals acting on a different pathway. Hence, There is more antiproliferative activity on cancer cells and lesser cytotoxicity to normal cells.

Good explanation Heidi....although the active compounds usually are administered at 10-20 times lesser doses (as you suggested as well), but the point is, still the difference in the rate of killing of cancer and normal cells is far decreased as compared to crude formulations. say for example, the dose at which 50% killing is induced in cancer cells, caused 5-8% death of in normal cells in crude; but the doses (10-20 times lesser) of the active compound inducing 50% death in cancer cells increased its toxicity in normal cells to 40 to even 70%!

What I believe is the synergistic role of other compounds in the crude formulation plays a role to protect the normal cell integrity at nucleic acid levels. Discuss this too please.

Abhishek,

You are right. The protection of the nucleic acid of normal cell, often is triggered by damaging compounds, like caffeine, (hence you are correct depending on the compounds) the normal cells "stop" (and here I'm fuzzy, I think/remember? they stop DNA replication) while cancer cells keep growing and hence are more susceptible to DNA damage from these type of drugs, many of 1st and 2nd line cancer drugs cause serious DNA damage. This is why caffeine is ok for us older guys (we're not growing fast), but can do serious damage for fast growing fetus. In radiobiology (yrs. ago) we used radiation or Caffeine to cause mutations and nucleic damage in experiments. Also, if I remember correctly, in adults the steroid hormones are very protective to normal cells to many noxious chemicals. But, you could just as easily have a "formulation" that works in a way that causes more harm to normal cells than the cancer cells, favoring those #%@ cells!, depending how the cells react to the up/downs dose/triggers.

The synergy of other compounds is a difficult discussion because if we knew which level/doses of compounds that affect My-c, p53, RAS, etc... and all these other genes/pathways and how to best tweak them "together' up/down, then we could slam most cancers, while protecting the normal cells. If I could "really" answer this question I'd get Noble prize (it'll come together through a lot of people, I think). And yes, the other compounds have synergistic role; even if it a minor role is getting "drug" through cell membrane, adjusting pH, or in eating a plant through the stomach without acid degradation. Think of the AIDS virus, the best is "a cocktail", and that's just for a "virus" and we have so much more complexity in our system and the cancer cells have all that to draw on.

Although, it is in another discipline, the new lower cost of sequencing the genome, hence putting "together" the whole picture will eventually (already has) help in cancer drug development.

Heidi

I totally agree with the theory of synergism.

The fact that Rajaram explained about various components of a crude formulation triggering more than one pathway is legitimate. And also what Heidi mentioned about the noble prize question of synergistic activity (LOL!) is quite true. Its vast .....very vast and complex to draw down the complete web of action in a cell. like as Heidi you meant that a drug no matter how good it is if not able to penetrate the cell membrane loses its overall efficacy; though with the help of a fellow compound (in the formulation) which may help it get through by increasing its solubility or, manipulating the pH, etc. It is only going to help when we pen down these fragmented thoughts of ours together on a single sheet.

Now again take the example of the traditional medicinal practices like "Ayurveda" etc., where the practitioners (that time) never provided one single plant or derivative as a medicine but they rather made complex formulations involving dozens of plants, which probably complied with their beliefs of theory of Synergism which all four of us mentioned. I adore and wonder how hundreds of years back these guys were sure what herb works where n how, without a western blot PVDF or a Real time!

Ayurveda is very sophisticated. . I recently learned that a single herb (Guduchi leaf) can be extracted in different ways to target different ailments. One type of Guggulu can be adminstered with different vehicles (Anupanas) to target different tissues. There are 20 types of diabetes and at least 15 stages of asthama..talk of personalized medicine !! This is just amazing, and the word needs to get out. Yet its v. hard to get journals to accept papers on such topics! So, AYurvedic pharmacology must be understood. Perhaps, CHinese medicine and other traditional Meds have these approaches as well?

You are absolutely right about the statement of "word needs to get out" and the publishing part is rather more ironic! The natural active compounds have shown precise activities but they behave differently in a balanced manner in the formulation which mother nature has constructed for them, i.e., the crude extract. In an order to minimise the adverse effects whatsoever, other compounds have to be coupled or introduced along with the natural compounds....phew! Herculean task to know the perfectly effective formulation.....but whats wrong with the crude extract?

Crude extracts are cool ! But crude extracts are complex, and good chemists and biologists need to team up to work on this. The solvent and temperature used for extraction also matters a lot. We used aqueous extracts (to mimic Ayurvedic methods) and found good anti-arthritic activity...got it published after arguing politely with reviewers! But, the results from aqueous extracts did vary. We could reduce variation by controlling age and storage method of our herb powder. In fact, we could show loss of potency of the herb by a simple enzyme assay...so this helped us with Quality control of our herb powder. This approach can be used for Herbal Industry QC also. I have tried (without success), to get Industry scientists to take this up. To my knoledge, Industry only does HPLC-they dont have a " in vitro potency assay" for bio-activity of the herbs they sell. Hope this helps!

For Heidi and others: Can you explain and /or give example of steroid hormones protecting normal cells from noxious chemicals? I remember reading of protective effects of estrogen..its a mitogen which pushes cells to divide..by turning on certain transcription factors....The androgens work similarly. But, target cells would be limited to those in breast, ovary, testes etc....what about other normal cells? Any other mechanism by which steroid hormones can protect normal cells? I guess these normal cells would have to express the necessary steroid hormone receptors.