Mechanism of gemcitabine resistance in pancreatic cancer.

Gemcitabine is a antimetabolite anticancer agent and deoxycytidine analogue. It is the first line drug of choice for pancreatic caner. However its resistance is a major cause of concern. One of the mechanisms was discussed in previous post was over production of cytidine deaminase that chemically deactivate it. In this post I am going to discuss tumor environmental factors associated with gemcitabine resistance.

Pancreatic cancer is one of deadliest cancers with more than 90% of mortality rate as per WHO. There are two mail reasons for so. One is delayed diagnosis i.e
most of the cases symptomatically diagnosed after stage III. Second one is the complex microenvironment that is a formidable barrier for chemotherapeutic agents. The key phenomenon is the tumor environment is desmoplastic reaction. Pancreatic tumor consist of a mixture of cells such as tumor cell, fibroblasts, immune cells, mast cells etc. Tumor at the initial stage activates the fibroblast cells which are also known as pancreatic stellate cells. This activation leads to proliferation of fibroblasts and over production of extracellular matrix proteins (ECM). This phenomenon of fibroblast activation and resulted desmoplasia is termed as desmoplastic reaction. Increased accumulation of ECM proteins constricts both blood as well as lymphatic capillaries which results in increased fluid accumulation and increases the intratumoral pressure. Increased intratumoral pressure consequences reduction of blood flow to the tumor tissue. All these factors restrict permeation of chemotherapeutic agent to the site of tumor as discussed below and cause resistance.

Thus once chemotherapeutic agent for e.g. gemcitabine enters in to systemic circulation its accumulation in pancreatic cancer is restricted by several barriers. First one is decreased blood flow at the site of pancreatic tumor. The lower amount of gemcitabine those reached to the site has to cross the real physical barriers such as extracellular matrix proteins and and fibroblasts to reach to tumor mass. Collectively above factors renders a huge reduction of drug reaching to tumor site and lead to resistance.

In this perspective anti-fibrotic drugs are demonstrated to be useful for reversal of gemcitabine by disrupting the physical barrier.

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Refractory Pancreatic Cancer: Tumor micro-environment the actual culprit.

The complexity of cancer progression can be well observed when we consider a mass of pancreatic tumor progressing. Microenvironment; role of immune system, inflammatory response and fibrosis involvement are the key players modulating effectiveness of anticancer drug (e.g. Gemcitabine). In a study Weizman et al. demonstrated nicely how presence of monocyte/marcophase develop resistance of pancreatic cancer cells to gemcitabine. In mouse models TAM (tumor associated macrophases) induced production of enzyme citidine deaminase, an enzyme that causes inactivation of gemcitabine in a paracrine manner. Macrophsase colony stimumating factor inhibitor not only decreased the production of the enzyme but also resensitized the cells to pancreatic cells to gemcitabine.

In additions other microenvironvental factors responsible for gemcitabine resistance in pancreatic cancer will be discussed in future.

Formulating a drug in to nano-formulation will improve activity of cancer chemotherapy- is it a rule of thumb?

In second case when the drug is lipophilic: at all instances improvement of activity upon nano-encapsulation is expected as it increases aqueous dispersibility.
Under experimental conditions lipophilic drugs are dispersed in a carrier (such as DMSO, CremphorEL etc) those increase their water dispersibility. Under these circumstances, carrier at certain concentration promote nano-dispersion of lipophilic agent. Thus when nano-formulation of lipophilic drugs compared with respective carrier dispersion in terms of activity, there might not be significant improvement. It does not mean formulating them in to nano-formulation is not recommended, its just that we are comparing nano-formulation with other standard nano-dispersion and an equivalent activity justifies the nano-encapsulation.

The activity will be found to be much enhanced if no lipophilic solvent is adopted where much of the lipophilc drugs will be precipitated. However drugs in nano-formulation remains in dispersed state.

In a special consideration under in vivo experimentation, EPR effect mostly decides the fate of selective accumulation, as the release will be much slower and only factor contribute better efficacy is accumulation of drug containing formulation at the site of action. Otherwise, although nano-formulation improves aqueous dispersibility it will be of no use.

There fore,
-activity nano-formulation containing lipohilic drugs should not be concluded from in vitro results.
-under in vivo conditions, improvement of activity solely dependent on EPR effect.

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Formulating a drug in to nano-formulation will improve activity of cancer chemotherapy- is it a rule of thumb?

To understand this lets consider a case of a hydrophilic drug. Since at free state the treated drug is aqueous soluble, the most probable mechanism of cellular accumulation is concentration gradient dependent passive diffusion. However, here the inflow as well as outflow by endo-cytosis cannot be ruled out. This remains valid for both in-vitro as well as in-vivo conditions.
On the other hand, when a hydrophilic drug is encapsulated in to a nano-formulation, we are certainly gaining some benefit but there are some hidden constraints as described below.
-Under in-vivo condition cellular accumulation of drug majorly restricted to either passive diffusion or endo-cytosis depending release of drug. In case drug is released faster, free drug reaches to cite of action faster than the drug in nano-formulation. Thus its uptake is almost equivalent to that of free drug but a higher dose of encapsulated drug is certainly needed to get the same concentration. Hence there is no-advantage of formulating in to a nano-formulation.
- In the second case if the drug is released slowly under in-vivo conditions, nano-formulation with drug will reach to the site of tumor and accumulate specifically at the site (only if EPR effect remains valid). In these conditions, the dose administered is utilized in an ideal manner. Released drug as well as encapsulated drug remains available for cellular uptake by passive diffusion or endo-cytic uptake. Although a higher dose of encapsulated drug may be needed to achieve the desired site specific concentration, it will give desired effect for a longer period of time. Thus controlled release and EPR effect are essential for beneficial use of nano-encapsulation.
-In contrast to above two, under in-vitro conditions at a given dose, the barriers for drug activity is much. Both the encapsulated as well as un-encapsulated drug is readily available for cellular uptake by passive diffusion as well as endo-cytosis. But drug is available for biological activity only after release. If 100% encapsulated drug is released rapidly, the effective concentration will be equal to that of same dose at free form. However, due to prolonged feature of nano-formulations, there is a much higher chance that the total effective drug concentration will be lower in comparison to that same dose treated un-encapsulated drug. Thus irrespective of drug release after encapsulation the effective concentration up on treatment with nano-formulation is tend to be lower than similarly treated un-encapsulated free drug. In this case, the higher activity up on encapsulation is really questionable.
Therefore considering above possible effect on encapsulation, hydrophilic drug encapsulated in to nano-formulations will tend to show beneficial effect if only associated with EPR effect under in-vivo conditions. However under in-vitro conditions, there very minimal chance of effect enhancement, mostly it tend to remain the same or low based on release (fast or slow respectively).

Your Body is Acidic.Here is What You Need to Do (The Truth Behind Cancer You Will Never Hear From Your Doctor… )

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Treatment of cancer; where is the exact position we stand ?

Previously we have won the war against the endemic diseases such as TB, polio, Malaria, etc because scientific world understood the cause or causative organism and also found an or a group of effective drugs really working for them. That's just understanding a particular microorganism. However in case of cancer the real understanding involves a countless steps ahead, where at each level of anatomical hierarchy complexity are added up. Starting from cellular physiology, physiological interaction at each level such as  tissue, organ and body increased tremendously,  mediated through regulatory small molecules, enzymes, proteins, and ions. However we have very limited understanding of these interactions and physiology. Since till date scientific studies indicate cancer to be a wilder disease linked to cellular physiology, thus basic understanding of how cell function is essential to find out what went wrong. 
Treatment options available so far is analogous to recent French and Russian attach on IS, i.e. we have to destroy the establishment irrespective of the fact that there's always a mixed population get effected general public along with IS. The objective of statement is there is very limited distinction between normal and cancer cells those are being targeted by chemotherapeutic options available so far.

To summarize it has to be noted that we need to have the basic understanding of the cellular physiology to find out and rectify what resulted in cancer which we are dearth at. Thus I must say we still stand far behind the point from where problem can be understood and  solving the problem is still distant.

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Does obesity caused back pain??

The answer is yes. To some extent it is true. If you look at he human spine who don't have back pain looks like "J". But because of lack of proper muscle strength and habits to hold it in the particular shape make the spine to become like "S". It has been observed that if you have big belly or fat deposition that actually weaken the back muscle and results in an extra curve in the spine which generally leads to back pain.
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Enzyme combination for wound healing and inflammatory conditions

1.  Trypsin: Needed for improving digestion. In the process of wound healing it mainly works for removal of dead tissue. 
2.  Bromelain: Bromelain is an enzyme found in pineapple juice and  stem. Bromelain is used for reducing swelling (inflammation) in surgery or injury. It is also used for hay fever, treating a bowel condition that includes swelling and ulcers..
3.   Rutoside Trihydrate: It is known as Rutin. Rutoside Trihydrate is mainly found in many plants, including Buckwheat, Tobacco, Forsythia, and Viola etc. It has been used therapeutically to decrease capillary fragility.
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