Hi abhishek,

I think the reason behind this is the cell's resistance to the doses.If you proved the dose for a longer period of time then some cells tends tend to get resistance and the effectiveness of the radiation goes down, similarly if u double the doses , the cells which gets resistance to it tends to be alive and multiply and the other cells die, so the number of resistance cells increase, decreasing your dose effect , eventually

Besides Resistance development ... there may be substrate inhibition from ur plant extract .. check biochemistry behind their action ...

If I could add a think, probably all that you described act, and it's the problem to evaluate complex biological systems, first in vitro and how to extrapolate in vivo.

I think you have also to consider the general response of a biological system (or organism) in term of statistic laws.

Repartiton of individuals in a population is most often following a Gauss curve centred on mean; sometimes (ie red blood cells) according a Poisson curve.

And the response to a treatment also, because, as said by Dipon DAS, you mesure a mean effect on a "population" of responders.

Even without resistance, simple disponibility to all individuals according to the dose administred can modify the response; also elimination (steady state between absorption and exflux); also "saturation" of receptors needed for the action. And so on...

Regards

Didier JAMBOU

@Dr. Jumbou ... sir can you please explain your last paragraph with little more details ??

@ Dr Rohit Suratekar,

Dear colleague,

Most dose/ response curve (applicable to different biological systems) , in a one compartiment model of distribution, shows an asymptotic aspect with a steady-state and maximum effect even increasing doses. The reasons can be variable (ie in enzymatic reaction, it's saturation of the catalytic site of enzyme).

In Pharmacokinetic, and a two compartment models of distribution (the most usual), the aspect of curves varies and can be represented by equations (I am not a specialist). Sometimes, the form of curve is not asymptotic, but parabolic, as you describe. This can be find also in cell cinetic in vitro and the interpretation can be numerous.

All these data are for one "individual" , and in a population, the observed effects are the mean of all individuals.

I'll ask to a friend, specialist in pharmacokinetic , the explanations when you have a parabolic curve in dose/response.

And perhaps colleagues in the group "simulation" could also explain it to us.

Regards

Didier

@ Dr. Jambou ... that is all correct for normal cells ... but as we are testing this against Cancer cells ... it is not that the growth curve and response curve will be different from normal cells ??

Because they have many growth factors and other enzymes besides high metabolic rates .

Is it not that Clearance of Drug will be more in case of cancer cells ?

I guess Rohit meant "Product Inhibition" in Biochemical reactions' inhibitory pathways. Yes this may be the case that Amount of dose of plant extracts when increased is prohibiting its own action. But can we narrow it down more and can there be any other reason?

You are right (ie MDR genes possibly activated in cancer cells playing role in exflux of drugs).

Even if characteristic of cancer cell/normal cells are different, solely regarding to simple kinetic phenomenon, the complexity of mesuring a population is depending on the mode of action of drug (surface receptors, cell entry needed and intracellular action).

My considerations concerned the general case of a dose-response curve. In the case of cell growth, evidently, the first hypothesis with a parabolic curve is toxicity dose-dependant(simple one or apoptosis stimulation).

If you think that your curve is due to a specific mechanism of action, you have different cases:

If surface action acts: increasing external concentration of drug can saturate the receptor (and you have an asymptotic curve), or by contrast the drug can be all "consummed" (of fixed) if number of receptor increase (inducible synthesis), or not sufficient to sature all receptors, and the effect decrease âpparently with dose (you have a parabolic curve).

If you have an intra-cellular mode of action , the exflux can be involved (MDR genes activation).

So, if you want to know if these processes are involved or not to explain your kinetic, you have ie to ensure that concentrations of drug external to cells are constant during time and sufficient, and not decreasing.

If you want to explain your responses, you have to envisage all possibilities.

Best regards

Didier

@Abhishek ....

It may be Product or Substrate inhibition ....

There is chance that ur extract itself inhibiting uptake of drug ..

We cant say sure unless we know about its biochemical pathway and receptor-product (or substrate) structure and their interaction of course ... This will be another PhD topic .. ;)

But if you want to minimize it you should know the mechanism behind drug ...And there will be hundreds of reason behind this Like Dr. Jumbo explained in his post ...

You may get idea from present Literature...

@Dr. Jambou ...

Yes .. there will be hundreds of mechanisms for resistance to drug ...

So it will be hard to comment directly from Kinetics curve ... also we dont know what is action of this drug , where it acts , whats its pathway , how drug differentiate Host cell from target cells ...