Most chemotherapeutics given in the clinic today interferes with replication in some manner, either by damaging DNA or acting like nucleoside analogs (both often cause S-phase arrest), or they prevents mitosis by stabilizing the cells microtubules, thereby possibly triggering the spindle assembly checkpoint. As cancer cells undergo rapid cell divisions they are generally more susceptible to these drugs than normal cells. On top of that, cancer cells often have impaired ability to recognize and/or repair DNA damage, which increase the chance that they cannot properly replicate their DNA, eventually causing cell death by mitotic catastrophe or by apoptosis. Unfortunately, resistance is common, and the drugs also interferes with normal cell divisions, hence the commonly observed hair loss among patients that receive chemo (and other under-the-skin effects, like low blood counts due to reduced production of new blood cells).

Next generation targeted drugs may have fewer side effects though, as they are supposed to more accurately target e.g. overexpressed receptors, or proteins that are very rare or never present in normal cells (like testis antigens and fusion genes, the BCR-ABLE targeting Gleevec being probably the most famous one). However, these drugs are still largely either in clinical trial and thus not availably for most patients or fairly rare in common clinical use, with a few well-known exceptions like HER2 targeting Trastuzumab, various EGFR inhibitors, a few PI3K inhibitors and above-mentioned Gleevec.

To make a long story short, if you kill normal cells as well as cancer cells, you cannot use the drug as an anticancer agent in the clinic.

http://www.youtube.com/watch?v=FBLnL4XA6fc

There must be a difference in killing rate between normal cells and tumor cells. This difference can be small, but it must exist. The smaller the difference is the heavier are the side effect on healthy tissues and the patient.

For equal killer rates no therapeutic application is possible.

@ John

True, but you have to admit that the large majority of the drugs used in the clinic do not target a specific protein overexpressed in cancer cells. And in many cases this targeted strategy fails because of the selection of cells that do not express the target anymore.

Most chemotherapeutics given in the clinic today interferes with replication in some manner, either by damaging DNA or acting like nucleoside analogs (both often cause S-phase arrest), or they prevents mitosis by stabilizing the cells microtubules, thereby possibly triggering the spindle assembly checkpoint. As cancer cells undergo rapid cell divisions they are generally more susceptible to these drugs than normal cells. On top of that, cancer cells often have impaired ability to recognize and/or repair DNA damage, which increase the chance that they cannot properly replicate their DNA, eventually causing cell death by mitotic catastrophe or by apoptosis. Unfortunately, resistance is common, and the drugs also interferes with normal cell divisions, hence the commonly observed hair loss among patients that receive chemo (and other under-the-skin effects, like low blood counts due to reduced production of new blood cells).

Next generation targeted drugs may have fewer side effects though, as they are supposed to more accurately target e.g. overexpressed receptors, or proteins that are very rare or never present in normal cells (like testis antigens and fusion genes, the BCR-ABLE targeting Gleevec being probably the most famous one). However, these drugs are still largely either in clinical trial and thus not availably for most patients or fairly rare in common clinical use, with a few well-known exceptions like HER2 targeting Trastuzumab, various EGFR inhibitors, a few PI3K inhibitors and above-mentioned Gleevec.

@ Nicolai

As you said, most chemotherapeutic agents target dividing cells. But blood cell progenitors or intestinal cells divide more than most cancer cells. I see four possible explanations why these chemotherapies can be used. The first one is that normal tissues with high renewal rate are organized with a stem cell compartment which is protected, whereas most cancers do not have a "true" stem cell compartment. The second one is , as you said, that cancer cells may have more difficulty to repair DNA or to arrest their cycle. The third one is that some immune responses that are triggered upon chemotherapy induced cell death are specific for cancer cells. The fourth one is that, empirically, we have selected drugs, which, for unknown reasons make the distinction between normal and cancer cells.

I don't know about the stem cell part, that remains a topic of intense research. However, both blood and intestinal cells are also affected by chemo, common therapeutic side effects like neutropenia relate to these issues. But the drugs are given in concentrations that are (supposed to be) lower than what can be tolerated by the patient (not necessarily lower than the growing cells can tolerate, these will then die off - remember, it's a gaussian distribution, you don't ever kill off all cells, neither normal nor cancer). If the cancer cells are generally is not sensitive to these concentrations, the drugs are ineffective. The other point is that the cancer cells often have lost or inhibited/deficient repair mechanisms or check points (they became cancer cells, hence they have "issues"). Thus, while the normal cells recognize the damage, and either apoptose or initiate repair, the cancer cells may not be able to do this. Even if they can completely stop their cell cycle, they might not be able to repair the damage in time, which can lead to cell death (possibly due to inherrent "pressure" to divide, activated signaling cascades that cannot be stopped-see e.g. Mike Yaffe's interesting paper in Cell 2012, on re-wiring of the growth signaling cascade to activate apoptotic pathways:

http://www.sciencedirect.com/science/article/pii/S0092867412004199).

If a cell goes into mitosis with DNA damage, like intra-strand DNA cross-links caused by platinum agents, or quadrahelical chromosomes caused by erroneous repair, the chromosomes will break up, and the cell will die.

You third point on the immune system is probably often very true, and is being explored a lot at the moment with the combination therapies being tried, where cytotoxics are added to the T-cell activating drugs, PDL-1 and CTLA-4 inhibitors. The basic idea is that the cytotoxics cause the release of cancer antigens, which can be presented to B-cells, and thereby activate T-cells. The above mentioned drugs then prevents the cancer from shutting down the immune response. This is really promising, by the way, impressive results have been coming out in the past few years. But for chemotherapy alone though, activation of the immune system is probably mostly limited, as far as I know, chemotherapy rarely cures anyone on their own (leukemias and testicular cancers notable exceptions), usually surgery is performed to remove the primary tumor. And for solid tumor cancers, no-one is cured with chemo once the cancer is metastatic (again, except testicular cancers).

On your fourth point, many chemo drugs have been empirically selected, at least to some degree. You can read up on the specific drugs and how they were developed into clinical use on Wikipedia. There's a nice article on the "history of cancer chemotherapeutics".

Thank you for your input Nicolai. Yes, I know that blood cells are actually sensitive to chemotherapy!

http://www.youtube.com/watch?v=FBLnL4XA6fc

I am not an expert, but read something like this. References are given here.

“Tumors have “leaky” blood vessels, which allow relatively large nano-sized “pills” to enter. This is called Enhanced Permeability and Retention (EPR) Effect. Normal blood vessels are not “leaky” and nano-particles are prevented from entering. This allows one to selectively target tumors.”

Abraxane® (paclitaxel protein-bound particles for injectable suspension), the first approved drug to use albumin nanoparticles to improve the therapeutic and safety properties of an anticancer agent.

Dan Peer, Jeffrey M. Karp, Seungpyo Hong, Omid C. Farokhzad, Rimona Margalit, and Robert Langer, (2007) Nanocarriers as an emerging platform for cancer therapy, nature nanotechnology, V. 2, pp 751 – 760.

Duncan, R. Nature Reviews Cancer 2006, 6, 688-701

Dear Divya

Although it is an effective treatment for many types of cancer , chemotherapy , as well as other cancer treatments can cause side effects . The types and intensity of side effects vary from person to person , depending on the type , location of the cancer , the treatment dose and health of the person .

Chemotherapy attacks the cells are actively growing a characteristic of cancer cells, but does not distinguish between normal cells in active growth (such as blood cells , mouth, intestines and hair) and cancer cells . Side effects occur when the damage of chemotherapy affect normal , healthy cells and keeps body functions and appearance. However , doctors and scientists are constantly working to identify new drugs , methods of administration ( drug dosing ) , chemotherapy and combinations of existing treatments that have fewer side effects . As a result , many types of chemotherapy are easier to tolerate than medications used to a few years . In addition , doctors have made ​​great strides in recent years in reducing pain , nausea and vomiting , and other side effects . During the treatment the oncologist responsible will work the best way to prevent or avoid these effects

Source : Oncology Center of Paraná - Brazil

Yes of course. Chemotherapeutic agents target both healthy, normal cells as well as cancer cells. I believe the general principle is that these agents target quickly dividing cells such as cancer cells but also gut cells and hair cells. These cells (cells lining the gut and hair cells) also divide quickly and are targeted as well. This is why nausea and hair loss are common side effects of these agents.

Dear Divya: The first thing to understand the pharmacodynamics of a drug, is to understand, how the drug attaches on the cell surface-chemoreceptors. More than often the chemoreceptors on cancer cells is different from those of normal cells. Therefore, the tailored drug molecule will preferably dock on the cancer cells and carry out their actions rather than on normal cells. True, as you have rightly pointed out, that these drug molecule can also attack the normal cells and bring about the damage, but then such docking of the drugs on normal cell receptors follow different dynamic principles.

As already was written above,

cancer chemotherapy inhibits replication of all cells. Thus quickly dividing cells (like hair follicles or gut epithel) are also demaged,

Though there are new therapies in research which specifically inhibit cancer cells

Some chemotheraputic drugs affect the blood supply and so slow the growth of cancer cells relative to normal cells. They essentially starve the quickly growing cancer cells by allowing less nutrients to reach the out of control cells and by interfering with the oxygen delivery to the cells. This mechanism involves constricting the blood supply and is not selective to cancer cells, however since the rate of growth for cancer cells relative to normal cells requires greater amounts of nutrients and oxygen for metabolic processes the cancer cells are effectively choked off. Avastin works in this way

Avastin is approved for:

Metastatic colorectal cancer (mCRC) for first- or second-line treatment in combination with intravenous 5-fluorouracil–based chemotherapy. It is also approved to treat mCRC for second-line treatment when used with fluoropyrimidine-based (combined with irinotecan or oxaliplatin) chemotherapy after cancer progresses following a first-line treatment that includes Avastin

Avastin is not approved for use after the primary treatment of colon cancer that has not spread to other parts of the body.

Advanced nonsquamous non–small cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel in people who have not received chemotherapy for their advanced disease

Metastatic kidney cancer (mRCC) when used with interferon alfa

Glioblastoma (GBM) when taken alone in adult patients whose cancer has progressed after prior treatment. The effectiveness of Avastin in GBM is based on tumor response. Currently, no data have shown whether or not Avastin improves disease-related symptoms or survival in people previously treated for GBM

Yes

By and large all Anti- cancer drugs affect the normal cells also, particularly actively dividing cells are more susceptible, hence chances of blood and skin disorders are more with chemotherapeutic agents.

Atif Hayat

isra university Hyderabad.

Yes chemotherapy affect the normal cell and stem cell transplant help in protection

To presume that it DOES NOT affect normal cell is behaving very nively. Of course the drug affects the healthy cells as well.

-Parimal

Dear Divya

Molecular mechanism of resistance to chemotherapeutic agents and concomitant toxicity in normal cells have been the focus of research for the past two decades. A group of signaling proteins called WNT has recently gained attention.

http://toxsci.oxfordjournals.org/content/136/1/183.short?rss=1

www.frontbiosci.org/2013/v18/af/4187/2574.doc

There are a number of designer therapeutic molecules being tested for reducing the toxicity of chemotherapeutic agents through the modulation of WNT pathway

while studying anti cancerous nature of a drug by MTT or wound healing assay or by any other assay,

i think it is essential to check the effect of that drug on normal cells also, as a control

There appears to be some confusion here about what is, and isn't, a chemotherapy agent so I will try to clarify, using consensus definitions represented over multiple national cancer evidence-based authorities, including in the US the FDA, NCCN and NCI, in the EU ESMO and St. Gallen, in the UK NICE and MHRA, in Australia the TGA, in Japan the JCCRI, and their multiple counterparts in Asia and Africa.

So, in breast oncology there are three classes of FDA-approved / NCCN recommended oncotherapeutic agents – agent with demonstrable anti-cancer activity – available, and these are collectively known as ONCOTHERAPIES (anticancer therapies):

(1) ENDOCRINE THERAPIES

which are hormone-based modulators of the endocrine system (the SERMS tamoxifen and toremifene; the aromatase inhibitors (AIs) like letrozole, anastrozole and exemestane; the antiestrogen fulvestrant; the LHRH/GnRH agonists, etc.).

(2) CHEMOTHERAPIES

which are definitionally preferentially cytotoxic (direct tumor cell eradication or damage (known as cell “kill”) against proliferative cells (although all may potentially adversely effect to a lesser extent normal cells, culminating in leucopenia, neutropenia, thrombocytopenia and/or anemia). In fact, it is often - incorrectly - assumed that chemotherapy agents are specifically designed to effect only rapidly proliferating (both dividing and multiplying) tumor cells, but this is not the case: many normal cells are also rapidly proliferative, such as cells in the bone marrow, oral mucosal cells, and hair follicles, among others, and when chemotherapies are deployed, myelotoxicities (leucopenia, neutropenia, thrombocytopenia, anemia) can result as collateral damage from toxicity to bone marrow cells, while mucositis, a common chemotherapy adverse effect, can result from damage to normal rapidly proliferating oral mucosal cells, and chemotherapy-induced alopecia from collateral damage to hair follicle cells, etc.

It is not that chemotherapy agents affect only tumor cells - these examples show otherwise - but it must nonetheless be the case that tumor cells are PREFERENTIALLY damaged compared to any normal cells affected. A subclass of chemotherapy, all of which must be cytotoxic, are genotoxic (DNA-damaging) agents: Thus not all chemotherapies, that is not all cytotoxic agents, are also genotoxic. Some are genotoxic: like alkylating agents (cyclophosphamide, etc.) and anthracyclines doxorubicin, etc.). But others are cytotoxic but not genotoxic (DNA-damaging), like the third-generation cytotoxics that include gemcitabine, capecitabine and vinorelbine, among many others. And in addition, some agents are non-cytotoxic but they are genotoxic: an example would be the biological agent class of PARP inhibitors, so these are not chemotherapies but genotoxic biological therapies.

Within chemotherapies, we have rich subclass: alkylating agents, anthracyclines, antimetabolites; antimicrotubules (taxanes and non-taxanes), vinca alkaloids, platinums, epothilones, among many other subclasses.

(3) BIOLOGICAL THERAPIES

(also known as “targeted therapies”), essentially biological response modifiers (including of immune function) via modulation of underlying molecular pathways (EGFR, VEGF, PI3k/AKT/mTOR, IGF, MET, WNT/beta-catenin/Hedgehog, JNK, ERK, APPK, BRAF, KRAS, HSP, HDAC, DNMT, Src, and many many others) implicated in oncogenesis (carcinogenesis or tumorigenesis), malignant transformation, or the metastatic cascade. There are many subclasses of biological agents like the anti-HER2 agents (trastuzumab, lapatinib, pertuzumab, and T-DM1), mTOR inhibitors (everolimus), anti-VEGF agents (like bevacizumab/Avastin which, note, is NOT a chemotherapy (cytotoxic) agent but rather a biological therapy with primary antiangiogenic activity for its therapeutic benefit), etc.

I have compiled as a dataset accompanying my paper ("Drug Interactions in Oncology - A Review") a list of Approved Oncotherapies in Breast Cancer, available on my ResearchGate Profile. I enumerate these agents within their defining oncotherapeutic classes, based on international consensus definitions aggregated from the organizations, colleagues and experts within the various oncology authorities I briefly enumerated above. The listing is comprehensive and inclusive of only agents with PRIMARY oncotherapeutic (anticancer) activity, not of agents used primarily for SUPPORTIVE oncology such as bisphosphonates (like zoledronic acid) and RANKL inhibitors (like denosumab) for bone metabolic health and reduction of SRE (skeletal related events), or such as growth support G-CSF agents to remediate neutropenia (like filgrastim and pegfilgrastim), since these are not anticancer therapeutics in their primary deployment. The Dataset also includes brief consensus definitions of the classes of oncotherapies.

Data Approved Oncotherapies in Breast Cancer - Definitions and Agents

Excellent question and a very instructive and instructive discussion that I have carefully read, from which can be a lot of good to know and that is very helpful for me!

My dear friend:  This is what is known as pharmacokinetic properties of any drug. 

The occurrence of intolerable side effects in patients undergoing chemotherapy is still a major clinical hurdle. Finding tumor-specific therapy and exploiting the differences between normal cells and tumor cells has led to strategies targeting oncogenic mutations or the deficiency of tumor suppressor pathways in cancers.

Contrary to achieving drug synergism when targeting tumor cells, one hopes to achieve drug “antagonism” on normal cells in a proposed strategy, termed “cyclotherapy.”1 The concept requires the use of two drugs, the first to arrest the normal cells and the second, to kill only cycling (tumor) cells The high frequency of p53 mutations in human cancers presents an opportunity for selectively targeting the p53-deficient tumors using S- or M-phase poisons, by activating a checkpoint arrest only in the normal cells. Indeed, several recent studies demonstrate that p53 activation protects normal cells from the toxicity of drugs acting in the S-phase or M-phase, including Ara-C,2 taxol,3 Aurora kinase inhibitors4 and Polo-like kinase inhibitors.5

References

1. Blagosklonny MV, et al. Cancer Res. 2001;61:4301–5.

2. Kranz D, et al. Cancer Res. 2006;66:10274–80.

3. Carvajal D, et al. Cancer Res. 2005;65:1918–24.

4. Cheok CF, et al. Cell Death Differ. 2010;17:1486–500.

5. Sur S, et al. Proc Natl Acad Sci USA. 2009;106:3964–9.

Following

Of course it does. That is why side effects occur during chemotherapy treatment