Dear Dipon DAS,

In parallel with cancer causes said by Amit Kumar Singh, drug resistance of cancer cells proceeds in different mechanisms which can act in all patients,ie (but not exhaustive):

- local condition of cancer cell growth (acidic conditions can inactivate some drugs),

- pharmacokinetic and metabolism of drugs can be variable in each patient,

- variation of drug diffusion in cancer tissue (necrotic area not accessible),

- induction of multidrug resistant gene in cancer cells (protein chanel increasing drug exflux from cytoplasm),

- according to each mechanism of action of the drugs: induction of cancer cell genes which bypass this action mechanism.

We could compare this phenomena to acquisition of antibiotic resistant by bacteria.

Best regards

Didier J

cancer is nt caused b'cz of just 1 cause..bt medicines focuses on just 1 target so in some cases dey r effective n in other dey r nt

It will be ineffective in other individual if it is targeted to specific DNA or RNA i.e. due to change in genetic makeup ...

Dear Dipon DAS,

In parallel with cancer causes said by Amit Kumar Singh, drug resistance of cancer cells proceeds in different mechanisms which can act in all patients,ie (but not exhaustive):

- local condition of cancer cell growth (acidic conditions can inactivate some drugs),

- pharmacokinetic and metabolism of drugs can be variable in each patient,

- variation of drug diffusion in cancer tissue (necrotic area not accessible),

- induction of multidrug resistant gene in cancer cells (protein chanel increasing drug exflux from cytoplasm),

- according to each mechanism of action of the drugs: induction of cancer cell genes which bypass this action mechanism.

We could compare this phenomena to acquisition of antibiotic resistant by bacteria.

Best regards

Didier J

According to "Phenotype = Genotype + Environment", the same cancer phenotype may own different genotypes and different environments, this is the key reason for an anti-cancer drug being effective in some individuals and ineffective in other individuals, and this is why personalized medicine was put forward to solve this problem.

what do you all suggest that should be common mechanism to combat cancer rather than targeting individual targets effecting individual patients.??

Presently common mechanism used in Cancer treatment is involving many factors like surface markers, metabolic rate, specific protein concentration , different activated genes etc. which is normally different from healthy cells.

Targeting individual is not possible , researchers are aiming something more common [ like in most of the cancers we take into consider P53 , P300 , VEGF etc concentrations which are different from normal cell ]

The problem is that there is not one cancer but some cancers. And it's because we haven't at present a global and solely solution to cure cancer.

And also because cancer development occurs in at least four steps (see precedent comments); and during evolution, the abnormal proliferation can stop at one step; and then we define lesions as pre-cancerous (dysplasia) and not yet declared as cancer; and without we could affirm that dysplasia obligatory conducts to cancer.

Finally, always remember that processes that conduct to cancer are first physiological ones necessary to the functionning of cells in certain circumstances (woundhealing ie) and we cannot completely inhibit thiese ones in all cells without important general side effects during treatment (that is often the case in treatment); and it is only dysregulation of these natural mechanisms that leads to cancer.

All preceeding explain because we have to be more and more specific to destroy cancer cells without altering normal cells. It is the base of new cellular treatments where we isolate from patients some cells of her/his immune system, "educate" them in vitro to recognize specifically cancer cells, then re-introduce in the body to treat.

According to the mechanism of a disease, we have the same problem to cure VIH disease because the virus infects the immune systmem and we are not able to produce a vaccine because vaccine use the immune system to act.

Best regards

Didier J

Considering the fact that different cancers result from different mechanisms of carcinogenesis and development, to late phase patients of cancers, radiation therapy maybe the common choice for therapy. Modern radiation therapy firstly localize cancer focus and the edge of its metastasis in vivo, then select different radiation dosages without harm to surrounding normal cells to treat cancer patients.

Unfortunately there is no expert consensus for a mechanism for initiation of cancer and early disease disease progression even after more than a century and a half of research by experimental and clinical oncologists worldwide. One of the problems is political, that there are five competing mechanisms of carcinogenesis, ie somatic mutation, epigenetic, mitochondrial, aneuploidy and tissue field theories. All of these theories have supporters who hold strong views that their theory is the correct one and that the others are wrong. In my view these theories are not mutually exclusive. Given the complexity and heterogeneity of many early tumor types I believe that all have a role to play in tumor initiation and early disease progression. What is needed for a major breakthrough in our understanding of cancer in my opinion is a new model of carcinogenesis -one that is at once both simplifying and unifying and accommodates the major elements of these five theories all of which have support in the literature. I think that this would lead to less competition and more cooperation and collaboration worldwide among supporters of these various schools of thought. Once we understand the early events in cancer we will be in a much better position to design new ways of prevention, early diagnosis and treatment.

I am totally right with Barry Barclay; and I think that we could consider that cancer mechanisms and their comprehension are an "existentialist problem" linked to life comprension.

Thank you for agreeing with me Didier but after I reread my comment I'm sorry it may have seemed more philosophical than I meant it to be. The group began this discussion about chemotherapeutic drugs and why they succeed in some cases and fail in others -so let me try to go back to that and try to be more specific. My view is that major differences in the response of tumors to chemotherapy is due at least in part to the heterogeneity of histopathological phenotypes of cell lineages within the emerging tumor mass. In my area of expertise if one looks at the response of cells to drugs like 5-FU one often sees the emergence of drug resistance by gene amplification, in many instances of the target gene TYMS. This is an old story. What seems to be emerging however is the notion that TYMS excess may not just be a selective ( possibly an adaptive) consequence of chemotherapy but that because the TYMS gene product is both a metabolic regulator and oncoprotein that TYMS dysregulation may just be causally related to certain types of tumor formation in the first place. This is a novel way of thinking about an old problem because some of the tumor cells will respond well to 5-FU not just because of differences in host cell cytotoxicity within the tumor mass but also by lowering TYMS activity with the drug the tumor phenotype was reversed during treatment but returned to a malignant state once the drug was withdrawn. Clinically there would be an initial favorable response followed by relapse in some tumor types (those caused by TYMS dysregulation) but not in others, that arose from another causal mechanism.

Oh Barry ! I didn't want to suggest that your comment was more philosophical that a real response; and so not sufficiently precise. But I think that comprehension of cancer mechanisms can lead us far away because ilnked to the functionning of mechanisms of life in general.

And your precise response give us a good example of possible explanation of drug resistance: selection of tumor cells with capability to bypass the drug mechanism of action,as general selection process occur in species according to Darwin? but with the difference that these resistant cells exist already at the beginning of tumor development (and in this case more similar to the functionning of immune system); up-and down-regulation mechanisms as receptor functionning in general, adapting their synthesis to ligand concentrations ? or directly gene regulation as a natural phenotype expression changing existing in normal cells (ie smooth muscle cell phenotype changing from secretion to proliferation in some circumstances; that is also an adaptation mechanism to modifications in environment, because necessitated by wound healing in this case)

Best regards

Didier

Drug resistance is a very common problem of cancer drugs, but instead of chemotherapeutic drugs, can't we look for some other ways to treat cancer because as Dr Didier mentioned, drugs not only target cancer cells but normal cells too, so the rate of side effects is very high in those cases. Similary like our lab working on natural anticancer drugs and also looking for alternative medicine,proves to very effective in treating patients but none are 100% effective and specific to particular types of cancer like breast or colon.Cancer may cause via various way biut I think that they have a common mechanism to amplify themselves which is irrrespectively similary in case of all cancer types and cell lines.

There are many different types of cancer treatment besides Chemotherapeutic drugs ... like Adenovirus Therapy , Gene Therapy, Radiation therapy, Photodynamic Therapy , Surgical Therapy, Reolysin drug therapy , Hybrid Therapy etc. Even now a days there are some vaccines for Cancer like HPV Vaccine [ against Cervical Cancer], HBV [ against Liver Cancer ], Oncophage [ Personalized Cancer Vaccine ] . Though these needs still ore development , there are so many different ways besides Chemotherapeutic ...

I like the previous comments by Didier Dipon and Rohit very much and agree with all of them. I would like to try to respond to each.

@ Didier I agree completely. After 30 years in this business I am just now beginning to appreciate that cancer in many ways can be considered as an evolutionary process in microcosm ie at the molecular cellular and tissue level rather that at the organism population level. Having said that it seems to me that tumors as emerging life (albeit pathological and parasitic in nature), individual tumors access whatever resources they have at hand to survive, adapt and evolve. eg by accessing developmental gene products (like morphogens) long silenced since embryogeneisis and organ formation, and by the use of wound healing inflammatory and other host responses that aid rather than inhibit tumor growth and invasion.

It is also becoming more clear how tumors use the two most powerful tools in evolutionary biology ie increased rates of mutation and recombination to generate the genetic novelty that selection forces in the local microenvironment act upon to produce the histopathological subtypes observed in the clinic. What is not well understood at all though is how tumor suppressor genes and oncogenes cooperate and collaborate once selected. We need to understand those interactions much better.

@Dipon I think your comment is insightful because we are still using variations on a very old theme as first line treatments for various cancers ie chemotherapies based upon cytotoxic drugs with a poor therapeutic index ( but large markets). As you say we need more less genotoxic treatments that are more effective and have fewer side effects.

@ Rohit. I agree with you also but at the risk of being cynical (a consequence of old age I'm afraid) I would argue that cancer has become big business and we need to devote much more human and financial resources on prevention. I say that as someone who has worked in the private sector for many years. We need to lower the rate of high risk behaviors ( eg smoking, excessive alcohol consumption) and develop many more prophylactic measures like vaccines as you say and also to develop cost-effective dietary interventions to counteract micro-nutrient deficiencies like folic acid and vitamin B12..

Dear Barry,

Very good analysis.

And finally, but perhaps more difficult with our actual knowledges: re-differentiate cancer cells in normal ones. In this case, no side effects of treatments, whatever they are. Already done in rare cases, where mechanism is relatively unique and better known(ie promyelocytic leukema and retinoic acid); but for the majority of tumours, necessiting a better comprehension of mechanisms.

Comparing to humans, it's "new education" of cells that moved away from the "right road", htat is conserved the body they take part.

In the evolution, parasites "undestood" this compared to virus, killing their host (probably a little anthropomorphic :) )

Best regards

Didier

Cancer nowdays has emerged more not because of the evolution or genetic reasons, but based on our life style, for example colon cancer has emerged more because of the consumpition of red meat in huge amount.So food style matters a lot in case of cancer, and i will say more than 60% of cancer cases are generated because of the lifestyle we lead, not for genetic and evolutionary reasons.Therefore like AIDS , i think mass awareness is more important about the food style and the life style. Drugs are essential , but i think drugs of natural resources should be used with less cytotoxicity and side effects. Combination therapy can also be used in this scenario to decrease the IC50 value of the chemotherapeutic drugs.

Cancer nowdays has emerged more not because of the evolution or genetic reasons, but based on our life style, for example colon cancer has emerged more because of the consumpition of red meat in huge amount.So food style matters a lot in case of cancer, and i will say more than 60% of cancer cases are generated because of the lifestyle we lead, not for genetic and evolutionary reasons.Therefore like AIDS , i think mass awareness is more important about the food style and the life style. Drugs are essential , but i think drugs of natural resources should be used with less cytotoxicity and side effects. Combination therapy can also be used in this scenario to decrease the IC50 value of the chemotherapeutic drugs.

Cancer nowdays has emerged more not because of the evolution or genetic reasons, but based on our life style, for example colon cancer has emerged more because of the consumpition of red meat in huge amount.So food style matters a lot in case of cancer, and i will say more than 60% of cancer cases are generated because of the lifestyle we lead, not for genetic and evolutionary reasons.Therefore like AIDS , i think mass awareness is more important about the food style and the life style. Drugs are essential , but i think drugs of natural resources should be used with less cytotoxicity and side effects. Combination therapy can also be used in this scenario to decrease the IC50 value of the chemotherapeutic drugs.

Cancer nowdays has emerged more not because of the evolution or genetic reasons, but based on our life style, for example colon cancer has emerged more because of the consumpition of red meat in huge amount.So food style matters a lot in case of cancer, and i will say more than 60% of cancer cases are generated because of the lifestyle we lead, not for genetic and evolutionary reasons.Therefore like AIDS , i think mass awareness is more important about the food style and the life style. Drugs are essential , but i think drugs of natural resources should be used with less cytotoxicity and side effects. Combination therapy can also be used in this scenario to decrease the IC50 value of the chemotherapeutic drugs.

Dear Dipon Das,

Your hypothesis on major environmental reasons in cancer development is possible. But we cannot claim it to my mind because of two reasons:

- before a certain period, we cannot detect cancer at an early stage, and progresses in diagnosis methods aim us to detect them at a microscopic level in human, and also increase detection by program prevention; so the apparently increase in observed "frequency" of cancer could be due simply to increase detection; so I think that we have to attribute a statistic weight in clinical study for these frequency according to the date where studies were performed.

In the same way, we have not an estimation of this frenquency in the past (some diseases was not classified as cancer; and also Alzheimer was classified as dementia linked to oldery before new clinical classification); finally, OK ! probably cancer frequency increase now due to changing in our environment, but we have to prove it,

-the second fact is that there is always difficulties in science, especially in bioogy, to establish a direct strong cause/effect relation , because of different events occuring simultaneously with the one we mesure (ie theory saing that a beat of butterfly wing in Europe could provoque a earthquake in Japan ! simply this signifiing that all earth events could be linked).

It's the reasons why I think we have always to stay careful in our affirmations, but also we have to be openmind to all possible responses, and preferably after asking only one question at the same time.

Best regards

Didier

Thius is because the differences in

1. the targeted protein concentrations

2. binding efficiecies differences

3. differences in structures

4. secondary molecular interactions

some time a single cause some time a combination could effect the outcome as resistance or suscetibility to such drugs.

I will add a small byte to this discussion.

There are nitrosamine agents in Betel nut, which in alkaline conditions (and only alkaline conditions) of Lime, can prove to be a potent carcinogen causing mostly oral and esophageal carcinomas. Now when the cells reach metastasis.....they exhibit an acidic condition!

Eventhough we know the reasons but when we see the big picture ....this whole event is amazing!

Well the other day one M.Sc student was asking me about what happens when a carcinogen in its favorable conditions (like the example of Betel nut + Lime) is treated to cancer cells in vivo. I told, "either very few cells will die of toxicity mostly or nothing will happen".

The new paradigm for carcinogenesis that seems to be emerging in modern medicine and is clear in this discussion is one of multifactorial causality. By that I mean specifically that there are genetic factors (polymorphisms in genes like TP53 RB-1 BRCA1) lifestyle factors ( excessive red meat consumption, betel nut use, smoking, excessive alcohol consumption) dietary deficiencies (vitamin D, vitamin B12, folate, selenium) and exposure to any number of environmental genotoxins (pesticides, aflatoxin B1, asbestos, UV and ionizing radiation) or infection by viruses (HPV, Herpes simplex type VIII) or certain bacteria (Hylobacter pylori) so the old methodology of disease etiology of Pasteur and Koch do not apply here. There is not a simple causal mechanism for cancer but many and Koch's postulates do not apply. We need to take a more holistic approach if we are to achieve any major breakthrough in our understanding of the disease.

In otherwords it can be said that Pasteur and Koch's methodology i not Universal in the present date.

Hello Abhishek. Yes I think that is a fair statement especially as we approach the era of genomic medicine. All patients are not the same and should not be treated as such. A much more fluid model is required. One that acknowledges individual differences susceptibilities and responses to treatment. Problem is of course this is expensive and large amounts of data need to be dealt with.

Dear Friends,

Reading our discussion, I realise that some methods are used at present for genetic diagnosis of inherited disease (DNA chips) conducting to study named GWAS (genome wide association study), in order to correlate polymorphisms in gene with occuring risk of certain diseases.

Perhaps these technology could be now used for acquired diseases, as cancer, to explore wide genomic expression occuring in cancer cells compared to normal cells, and also directly in patients. These are powefull technics where until 300.000 mutations or SNP can be mesured at the same time.

Regards

Didier

Yes I completely agree Didier at least in the case of some types of cancer where we know that a mutator phenotype is operative. Mutation rates may be three orders of magnitude above normal so we need high throughput methodologies like the microchips you mentioneed to characterize numerous mutations per tumour.type.. We also need to develop an algorithm for various tumour histopathological subtypes based upon these genetic fingerprints to use as both diagnostic and therapeutic indicators and relate these to clinical outcomes.

Right, Barry.

Indeed, with this powerful new technology, algorythms and softwares are needed to run data.

Working on genetic risk factors in arterial and venous thrombosis, I am at present performed a review article on mutation and SNP described in this area, then I'll perform meta-analysis. So, to help clinicians, my aim is precisely to select relevant SNP and test them by DNA chips. Tests based on a modelisation after SNP selection in order to elaborate a genetic scoring in thrombosis, then simulation by software before verifying by multicentric studies.

The same could be tested in other fields as cancer.

And use of microchips has been already made ie in Hematology to propose new diagnosis classification for hemopathy (we can find some publications on the subject); but it could take some time to validate it for diagnosis before replacing or complete old methods.

Regards

Didier

A critical element may be the differences between patients in the sensitivity of their cancer stem cells to the treatment agent(s). This is why there is a great need for methods to measure this for individual patients. The problem has been that these cells are only a tiny fraction of the tumor and even of the marker-selected enriched populations. See papers of West, Strausbol-Gron, Lawton, and Djordjevic & Lange (from different labs).

Genetic and epigenetic factors Dipon..

Thats exactly what toxicogenomics and pharmacogenetics seeks to answer.. Individual genes involved in drug metabolism pathways and are not necessarily part of it tend to interact with drugs depending on individual genetic information.It therefore follows in a non predictive manner, that anticancer therapies are formulated based on general assumtions and not such individualistic idiosyncracy.

I agree wth Arthur Fernandes Sylva.

I think we have to distingish two sort of mutations:

- those which cause avered diseases as hemophilia, cystic fibrosis, muscular dystrophies ... mutations rarely unique (cystic fibrosis) and also rare in frequency. There general transmission are relatively well known and general population doesn't bear them,

- and polymorphisms which are onlyresponsible of an increase risk of certain diseases; born by all; and sometimes homozygous are as frequent as wild allleles.

Difference is essentially in term of frequency in populations; not in mechanisms.

In parallel, entire genome sequency finally performed 10 years ago permitted us to well understand importance of polymorphisms we all possess (consequently risks of numerous disease for all; but risk is only statistic , that's different from a disease as hemophilia).

And polymorphsims are also present in sequences that don't alter protein for normal cell functionning but i.e in genes conducting to variation in drug responses.

So now genetic studies has to be applied for individuals, to determined individual risks of: diseases (in particular cancers), responses to drugs (treatment of cancers, but also responses to anticoagulants, aspirine ...), to be useful for strategies in health care.

New studies as genome wide association study (GWAS), micro-array and proteomic, metabolomic ... could helps us in this way.

Best regards

Didier J

The science here is really compelling and the promise for translation to the clinic is enormous. One thing I would like the group to consider proactively is the ethical implications of this technology and the potential for abuse.For example I can see where insurance companies might develop actuarial tables based upon disease risk polymorphisms and to deny healthcare coverage to high risk groups.

Hello Barry,

I agree totally.

Especally because , as precedently said, a risk is just an increase of probability to develop a certain disease, but not a fatality like with inherited disease as Duchenne myopathy, often known during pregancy and where the child will suffer from it.

And all humans have risks for at least one possible disease (as all of us for cancer); it's the "price of life".

But the problem is when there is financial consideration, as insurances (have we to insure life itself ?).

If we demonstrate in the future that all human as a particular disease risk, this makes relative the notion of good health, and insurances couldn't exclude anyone for problem of health. And which score could apply insurances ? which diseases are more serious than another ? and conducting to a more important mortality ?

In this case, which interest to know genetic risks of disease if everyone has one ? To my mind, in term of public health, to adapt medicine and treatments to individuals and not in general.

Best regards

Didier

I only mention the ethical consideration as a caveat. On the positive side genomics promises to revolutionize the practice of medicine as I see it. I just wonder as a basic scientist what will be the clinical outcome of a diagnosticians ability to recognize an individual who has a high risk for a fulminating course for an otherwise simple infection because they have a co-morbidity factor in their genome. The theoretical possibility also exists to target specific microbial pathogens without -for the first time to my knowledge, killing off commensals, so that the normal human micro-floral ecosystem remains intact during antibiotic treatment. I wonder as an example if this might lessen the occurrence of secondary opportunistic infections?

i agree

Omics-Based Molecular (OBM) approaches certainly holds the key to the future of medicine, albeit currently fraught with teething problems, such as expertise, reproducibility and a host of other factors. Could it be that microbiomics for example, hold the future to infectious disease control (including inflammation derived cancers)? The question beckons for plausible answers..... May I suggest that a formidable alignment of basic science research and biomedical research may be the desired bedrock for novel discoveries in translational medicine.

The reason might be the cause of the cancer or the origin of cancer.