Some basic facts about cancer

  1. Cancer cells have lost their normal regulatory mechanisms that control the growth and multiplication of cells.
  2. Cancer cells have lost the ability to differentiate (which means specialization).
  3. Malignant cancer cells penetrate into new fabrics to create secondary tumors, a process known as metastasis.
  4. Chemicals known to cause cancer, are called mutagens.
  5. The cancer may be caused by chemicals, lifestyles (smoking), and viruses.
  6. The genes that are associated with the cause of cancer, called oncogenes. Genes that change when mutations, called proto-oncogenes.

signs of cancer

  1. Self-sufficiency of growth signals (e.g., through the activation of the oncogene H-Ras).
  2. Insensitivity to signals growth inhibitory (anti-growth) (loss of tumor suppressor retinoblastoma).
  3. Evasion of cells (apoptosis), programmed cell death (survival factors produces IGF).
  4. Limitless replicative potential (including telomerase).
  5. Prolonged angiogenesis (VEGF produces inducer).
  6. Tissue invasion and metastasis (inactivate E-cadherin).
  7. Inactivation of the systems that are controlled in response to DNA damage.

Phase of the cell cycle

  • Phase G1 (gap 1): the cell grows in size and prepares to copy its DNA in response to various growth factors.
  • S phase (synthesis): DNA replication, chromosome duplication.
  • Phase G2 (gap 2): preparation for cell division. Checking the copied DNA and restore the damaged copy.
  • M phase (mitosis): formation of the mitotic spindle and the division into two separate cells (cell division).

Monitoring the progression of the cell cycle CDKs

  • Progression through the cell cycle is controlled by cyclin-dependent kinases (CDK).
  • cyclin Binding with related kinases starts the cell cycle to another phase.
  • Present inhibitory proteins that can modify the action of cyclins. These include p15 and p16, which block the activity of the complex of cyclin D-CDK. Another regulator is p21, which is controlled by the tumor suppressor protein p53.
  • Excessive activity of cyclins and CDKs have been associated with many tumors. Excessive production of cyclins and CDKs or CDK inhibitors insufficient production leads to disruption of the normal regulation of the cell cycle.

cell death

Necrosis - is uncontrolled (pathological) cell death. There are many causes of necrosis including injury, infection, cancer, heart attack, toxins and inflammation.

Apoptosis - programmed cell death. It is used by organisms to control cell number and tissue size.

apoptosis Methods

Two ways of activation: 1) to the plasma membrane through the external ligands upon binding to the receptor of death or 2) through the mitochondrial pathway.

Binding of external ligands such as tumor necrosis factor receptor (TNFα), Fas receptor superfamily of TNF induces receptor oligomerization and the formation of a signaling complex that induces death. This complex recruits the adapter molecule via FADD (Fas-associated death domain), several molecules Pro-caspase-8, resulting in caspase-8 activation, which ultimately leads to caspase-3 activation.

The mitochondrial release of apoptogenic factors such as cytochrome c, Apaf-1, caspase-9-apoptosomny complex containing proteins and inhibitors apopoza, trigger the activation of caspase-3

There is a connection between the two paths. For example, caspase-8, leading to cleavage of Bid, Bcl-2 protein family, which moves into the mitochondria to release cytochrome c.

regulators of apoptosis

  • factors Bcl-2 family regulate caspase activation or negatively (for example, Bcl-2, Bcl-XL, MCL1), or positive (for example, Bcl-XS, Bax, BAD, BAK, BID).
  • Inhibitors of apoptosis proteins (IAP) retard apoptosis.
  • Ascending modulators are oncogenes, such as c-myc, which activates apoptosis in a manner which is important for the treatment of cancer.
  • Tumor suppressor p53 induces apoptosis in certain circumstances.


  • Cancer cells are often called immortal, because there is no limit to how often they can share.
  • The lifetime of normal cells is limited to 50-60 cell division. This is regulated by telomeres. Telomeres are the 3'-end of chromosomes. After each replication lost approximately 50-100 base pairs.
  • At some point, the telomeres are not effective, and the DNA becomes unstable, which limits replication. Cancer cells have an enzyme called telomerase, which maintains telomere length and thereby allows more DNA replication.

Invasion of tissue

  1. In malignant cancer cells cancer cells detach from the primary tumor site, enter the blood or lymphatic vessel, forming of metastasis sites.
  2. cells usually adhere only similar cells. The signals are transmitted to the cell surface via cell adhesion molecules (e.g., cadherins). Moreover, the cells are connected to each other by fitting them in the extracellular matrix (EM).
  3. Adhesion to the EM includes molecules, called integrins.
  4. Matrix metalloprotease protein destroys an extracellular matrix and so is important to leave the primary tumor site and attach to the secondary site.
  5. If the non-cancerous cells are separated from the extracellular matrix, it stops growing and starts apoptosis.
  6. The metastatic cells lacking cell adhesion molecules, so that they can leave the site of the primary tumor.


  1. Tumors - rapidly growing tissues, which should have a good blood supply.
  2. Angiogenesis refers to formation of new blood vessels.
  3. Tumor cells release growth factors such as vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF-2), which leads to germination and expansion of existing capillaries.
  4. In healthy tissues restoration of damaged tissues is controlled angiogenesis inhibitors such as angiostatin and thrombospondin.
  5. Blood vessels resulting from angiogenesis are abnormal in the sense that they are disorganized structure and have leaks.
  6. These cells represent the integrins on the surface to protect the newly formed cells from apoptosis.
  7. Before angiogenesis may begin to be broken basement membrane surrounding blood vessel (held by the matrix metalloproteinases (MMPs)).

Suppression of internal tumors: p53

  1. In response to DNA damage, oncogene activation, or other adverse events induced by the tumor suppressor gene p53.
  2. Various kinases phosphorylate p53, which help to stabilize it. Activated p53 leads to DNA binding and transcriptional activation.
  3. MDM2 serves to suppress the p53, which in turn is regulated by p14 ARF.
  4. p53 triggers cell cycle arrest in untransformed cells by cell cycle regulators such as CDKs.
  5. It also triggers apoptosis in transformed cells by Bax.
  6. Most tumor cells p53 is mutated and inactivated.

Drugs that interact directly with DNA

  • Alkylating agents.
  • They contain highly electrophilic group.
  • Form covalent bonds with nucleophilic groups in DNA.
  • Connect the N-1 and N-3 of adenine and N-3 of cytosine, in particular the N-7 guanine bases.
  • Prevent the replication and transcription.
  • Are useful as antitumor agents.
  • Toxic side effects.


  • Carmustine and lomustine are fat-soluble and can penetrate the blood-brain barrier.
  • Formulations decompose to form alkylating and carbamoylating.
  • The resulting isocyanate groups reacts with NH3 lysine inactivating DNA repair enzymes.
  • It alkylating agent reacts first with O-6 of guanine, and then N-3 of cytosine another chain.


Pt-alkylating agents

  1. Bind to DNA in regions that are rich in guanine units.
  2. Prohibit transcription.
  3. In a solution of Cl-ligands are exchanged for water, resulting in a positively charged ligands, which bind to DNA (with 7 or N-O-groups 6 adjacent guanine).
  4. It is leading to localized unwinding of the DNA.



  1. Ribonucleotide reductase inhibitors.
  2. The enzyme converts ribonukleotiddifosfaty in dezoksiribonukleotiddifosfaty inhibited by hydroxyurea.
  3. Inhibitors of adenosine deaminase, e.g. pentostatin.

Anticancer therapy based on hormones

Steroid hormones bind to nuclear receptors and act as transcription factors.

If the cancer requires a certain hormone, you can assign a hormone that causes the opposite effect.

As used: glucocorticoids (hormones involved in the biosynthesis of glucose, e.g., prednisone), estrogens, progestins (e.g., medroxyprogesterone acetate), analogs of luteinizing hormone releasing hormone (LHRH).

Drugs acting on the structural proteins

Mitosis - is an ordered series of events in which identical copies of the genome move in separate places in the dividing cell. Mitotic feedback is very important for this event. Filaments formed in the mitotic spindle of microtubules. Microtubules are cytoskeletal elements, present in all eukaryotic cells. They are composed of α- and β-subunits. As formation (polymerization), and destruction (depolymerization) microtubule important for correct cell division. Medicines that prevent polymerization / depolymerization of microtubules affect mitosis, induce cell cycle arrest and induce apoptosis.

inhibitors of tubulin polymerization

  1. Alkaloids from the Madagascar periwinkle.
  2. Taxol harvested from the bark of yew trees.
  3. Associated with the β-subunit of tubulin and accelerates polymerization.
  4. The resulting microtubules are stabilized by inhibiting depolymerization.
  5. Cell cycle stops at G2 / M. step
  6. Prepared semi-synthetically.
  7. Can not be taken orally.
  8. It causes multidrug resistance (substrate for p-glycoprotein).
  9. Efotilony are bacterial metabolites. They are not a substrate for P-GP.

Signaling pathways that are important for cancer

Members of Ras-family proteins belong to GTPases and participate in signal transduction within cells. When Ras «ON", it is subsequently includes other proteins that comprise genes involved in growth, differentiation, and cell survival. As a result of mutations in the ras gene can lead to a permanently activated protein Ras. Since these signals result in the growth and division of cells, overactive Ras signaling may ultimately lead to cancer.

 p53 / HDM2: tumor suppressor. p53 has many anticancer mechanisms function and plays a role in apoptosis, genome stability and the inhibition of angiogenesis. It is modulated by MDM2.

 PIK3: phosphatidylinositol 3-kinase. PI3Ks are a family of enzymes signal converters capable to phosphorylate the 3-hydroxyl of the inositol ring of phosphatidylinositol. PI 3-kinase activity have been associated with cell growth, proliferation, differentiation, motility, survival and intracellular transport. Class IA PI 3-kinase p110α is mutated in many forms of cancer. Activity PI 3-kinase significantly contributes to cell transformation and cancer development.

AKT: protein kinase B (PKB, Akt) is a serine-threonine-specific protein kinase that plays a key role in many cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration.

MAPK: mitogen-activated protein kinase (MAPK) - this protein, specific amino acids serine, threonine and tyrosine. They regulate cell function, including proliferation, gene expression, differentiation, mitosis, cell survival and apoptosis.

farnesyl transferase inhibitors

RAS signaling protein involved in cancer. Mutations in the RAS are found in 30% of cancer cells. The mutant RAS is constitutively active.

RAS signaling requires binding to RAS inner membrane. This is done by adding carbon chain farnesyltransferase.

tyrosine kinase inhibitors

Small molecule inhibitors of tyrosine kinase (or TKI) - the common name ending in «-nib». Usually it is taken orally. Side effects vary depending on what they inhibit enzymes (what is their purpose). Some of them are effective against cancer that is resistant to the majority of previous treatments.

Common name brand name type of cancer
imatinib Gleevec Leukemia, stomach cancer
dasatinib Sprycel Leukemia, AML
nilotinib Tasigna leukosis
gefitinib Iressa Lungs' cancer
Erlotinib Tarceva Lung cancer, pancreatic
lapatinib Tykerb breast cancer
sorafenib Nexavar Cancer of the kidney, liver
Sanitinib Sutent clear-cell carcinoma

Growth factor inhibitors: Targeting EGF receptor, TK receptor.

Overexpression altered epidermal growth factor receptor results in the formation of an oncogene (EGFR, family ERBB).

Abelson tyrosine kinase inhibitor (BCR-ABL).

  • Kinase BCR-ABL oncogene is the only responsible for a rare blood cancer.
  • Inhibition of Autophosphorylation BCR-ABL by Gleevec.
  • Processing transformed BCR-ABL cell lines Gleevec results in a dose-dependent reduction in tumor growth.
  • The antitumor effect is specific for cells expressing BCR-ABL.
  • Gleevec re-activate apoptosis in the cells of BCR-ABL.

Angiogenesis inhibitors targeting receptor VEGF, a protein tyrosine.

  • Elevated levels of fibroblast factors (FGF) receptor and the growth of vascular endothelial growth factor (VEGF) are associated with angiogenesis.
  • VEGF is regulated by several cytokines, such as transforming growth factor (TGF-β), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF).
  • Inhibitors are mainly aimed at the binding of ATP to other targets for kinase: platelet derived growth factors (PDGF-R), mitogen-activated protein kinase (MAPK), insulin receptor-like growth factor 1 (IGF-1R), protein kinase B (PKB), c-Src tyrosine, inozittrifosfatkinaza (IP3K).

Inhibitors of cyclin-dependent kinases, S / T kinase

  • CDK important to control the cell cycle (mostly at the G1 / G2 depending on, e.g., DNA damage).
  • Ser / Thr kinase
  • They are activated by cyclins and cyclin-dependent kinase inhibitors inhibited.

Inhibitors of matrix metalloproteinases

  • MMPs are zinc-dependent enzymes (proteases).
  • Extremely destructive enzymes that are involved in the remodeling of extracellular matrix or connective tissue.
  • MMPs include kallagenazy, gelatinases, stromelysins and membrane type (MT).
  • They inhibit angiogenesis.
  • Collagenase cleaved between glycine and isoleucine.

proteasome inhibitors

It is a unit for decomposition of damaged or misfolded proteins, but also decomposes the protein involved in the regulation. Proteins marked for degradation, ubiquitin labeled. Inhibition of the proteasome leads to accumulation of regulatory proteins such as Bax promoter of apoptosis. Accumulation of regulatory proteins leads to cell crisis and triggers apoptosis.

Cancer Treatment antibody

Destruction of tumor cells using monoclonal antibodies (mAbs) can be the result of direct action of antibodies (e.g., by receptor blockade), immune-mediated cell killing mechanisms, the delivery of the payload and specific antibody exposure on tumor vasculature and stroma.

Tumor antigens that have been successfully targeted include epidermal growth factor receptor (EGFR), ERBB2, vascular endothelial growth factor (VEGF), cytotoxic antigen 4 associated with T-lymphocytes (CTLA4), CD20, CD30 and CD52.

Serology, genomic, proteomic and bioinformatic databases were also used to identify antigens and receptors that are overexpressed in tumor cells or populations that are associated with gene mutations, defined as the driving forces of the proliferation of cancer cells (tumor markers).

The main purpose of clinical evaluation was to determine the antibody mAb toxicity and therapeutic efficacy either alone or as a delivery system for radioisotopes or other toxic agents. It is also important to estimate its specificity in vivo by determining its biodistribution in patients and to evaluate the ratio of the absorption of antibody in the tumor as compared to normal tissues. Twelve antibodies (2012), have been approved by the US FDA for the treatment of various solid tumors and hematologic malignancies, and a large amount of additional therapeutic antibodies are currently being tested in the early and late phases of clinical trials.

Nomenclature of monoclonal antibodies

The last syllable always - mab.

  • Next to the last syllable

▪ -u- people (100%). Panitumumab. 

▪ -zu - humanized (95%): Trastuzumab.

▪-SI - chimeric (65%): Rituximab.

▪ -o - the mouse, s - rat, -e - Hamster, s - the primacy: Tositumomab.

  • Previous syllable

▪ -tu (m) - for the overall tumor [-ma (r) - mammary gland, -pr (o) - prostate, -co (l) - colon, etc.)..

▪ -ci (r) - for the circulation: Bevacizumab.

antibodies goals

Target antiangiogenic mAbs VEGF Bevacizumab Tumor vasculature
VEGFR IM-2C6 and CDP791 Tumor vasculature
integrin αVβ3 Etaracizumab solid tumors
integrin α5β1 Volociximab Tumor vasculature
Signals growth and differentiation EGFR Cetuximab, panitumumab, nimotuzumab and 806 Tumor glioma, lung, breast, colon, head and neck
ERBB2 Trastuzumab and pertuzumab Tumors of the breast, colon, lung, ovarian and prostate
ERBB3 MM-121 Tumors of the breast, colon, lung, ovarian and prostate
MET AMG 102, METMAB and SCH 900105 Tumors of the breast, ovary and lung
IGF1R AVE1642, IMC -A12, MK-0646, R1507, and CP 751871 Glioma, lung cancer, breast cancer, head and neck cancer, prostate cancer and thyroid
EPHA3 KB004 and IIIA4 Tumors of the lung, kidney, colon, melanoma, glioma, and blood cancer
TRAILR1 Mapatumumab (HGS-ETR1) Tumors of the colon, lung and pancreatic cancer, and blood
TRAILR2 HGS-ETR2 and CS -1008 Tumors of the colon, lung and pancreatic cancer, and blood
RANKL denosumab prostate cancer and bone metastases
Antigens and stromal extracellular matrix FAP Sibrotuzumab and F19 Tumors of the colon, breast, lung, pancreatic, head and neck
Tenascin 81C6 Glioma, breast tumor and prostate


antigenic category examples of antigens Examples of therapeutic mAbs Types of tumors expressing the antigen
Hematopoietic differentiation antigens CD20 rituximab Non-Hodgkin's lymphoma
Ibritumomab, tiuxetan and tositumomab lymphomas
CD30 brentuximab vedotin Hodgkin's lymphoma
CD33 gemtuzumab ozogamicin Acute myelogenous leukemia
CD52 alemtuzumab chronic lymphocytic leukemia
glycoproteins EpCAM IGN101 and adekatumumab epithelial tumors
CEA Labetutsumab Tumors of the breast, colon and lung
gpA33 huA33 Colorectal cancer
Mucins Pemtumomab and oregovomab Tumors of the breast, colon, lung and ovarian cancers
TAG-72 CC49 (minretumomab) Tumors of the breast, colon and lung cancer
CAIX cG250 Carcinoma
PSMA J591 Prostate cancer
Folate-binding protein MOv18 and MORAb-003 (farletutsumab) ovarian cancer
glycolipids Gangliosides (such as GD2, GD3 and GM2) 3F8, ch14.18 and KW-2871 Neuroectodermal and epithelial tumors
carbohydrates Le hu3S193 and IgN311 Tumors of the breast, colon, lung and prostate

T-cell immune response

Induced T-cell immune response involves the formation of an antigen, T cell receptor and MHC (major histocompatibility complex). It is protein fragments and peptides processed by the cell (no need to be exposed to the surface). Then triggers an immune response (production of cytokines, cell lysis factor, and so on. D.)

Antibodies / T cell response

After penetration absorbed antigens (mostly dendritic cells) and proteins are decomposed inside. Fragments are presented on the surface in conjunction with the main histocompatibility complex (MHC). Non-automatic capsular polysaccharides or proteins activated B-cells through the B-cell receptor (BCR). The starting antibody - is predominantly low affinity immunoglobulin-M (IgM) abs. Repeated exposure causes a more rapid immune response. Antibodies preferably IgG or IgA class. They are generally much higher affinity.

 Likewise, in 10 000 times more cytotoxic T cells.

Receptor on B cells is membrane-bound immunoglobulin (BCR), which is able to recognize whole proteins. In contrast, T cell receptors (TCR) only recognize small peptides. B- and C-cells recognize different epitopes.

 In naive (unchallenged) populations of B- and T-cells there are cells capable of recognizing all epitopes.

When infecting antigen proliferate only relevant B cells which can recognize the antigen (clonal expansion). Similarly, T-cells undergo a similar activation.

Increased binding affinity antibodies (affinity maturation). During this process, there are many mutations in the hypervariable loop (somatic hypermutation). switching antibody classes can occur during this process

Cancer Immunotherapy: blockade immune breakpoints

Tumors lead to multiple mutations in gene products that can be recognized as superfluous and trigger an immune response to their purification. Immune breakpoints are inhibitory pathways of the immune system that are crucial to maintain self-tolerance and modulation amplitude and duration, physiological immune responses in peripheral tissues in order to minimize collateral damage to tissue. Tumors misuse immune breakpoint to avoid cleaning the immune system, in particular to avoid specific tumor antigen T cell responses. Immune breakpoints frequently triggered receptor-ligand interactions, and they can be blocked by antibodies or modulated recombinant forms of the ligands or receptors. These antibodies do not target the tumor cell, but target the molecules involved in the regulation of T cell immune system soldiers. The purpose of the immune checkpoint therapy is not whether to activate the immune system to attack specific targets on the tumor cells, and to eliminate the inhibitory pathways that block effective antitumor T cell responses.

Blockade immune checkpoints (II)

An important point is control immune cytotoxic antigen 4 associated with T-lymphocytes (CTLA4), which inhibits activation of T cells. Programmed cell death protein 1 (PD1) limits effector function of T cells in tissues. Increasing regulation of ligands for PD1, tumor cells block the anti-tumor immune response in the tumor microenvironment. In contrast, tumor destruction induced by immunotherapy, is often delayed or even preceded by a period of visible tumor growth. Only a portion of patients responds to blockade of immune checkpoints. In these cases, the tumor microenvironment may not be immunogenic. Combination therapy can then create an immunogenic microenvironment that responds to immune control therapy. Many of these treatments are limited toxicity.

Immune checkpoint mediated cytotoxic T lymphocyte-associated antigen 4 (CTLA4), is induced in T cells during their initial response to an antigen. CTLA4 induction level depends on the initial transmission signal amplitude-mediated T cell receptor (TCR). High affinity ligands induce higher levels of CTLA4, which reduces the amplitude of the initial response. Naive and memory T cells express high levels of CD28 cell surface, but do not express CTLA4 on their surface. Instead CTLA4 is sequestered in intracellular vesicles. After TCR starts when antigen detection, CTLA4 is transported to the cell surface. The stronger stimulation through the TCR (and CD28), the greater the amount of CTLA4, which is deposited on the surface of T cells. Consequently, CTLA4 signal functions as a damper to maintain a constant level of T cell activation in the conditions of widely varying concentrations and the affinity ligand to TCR.

The main role of the path programmed cell death protein 1 (PD1) is not in the initial stages of T cell activation, but rather in the regulation of inflammatory responses in tissues effector T cells that recognize antigen in peripheral tissues. Activated T cells are activated PD1 and continue to express it in the tissues. Inflammatory signals in tissues induce the expression PD1 ligands that inhibit the activity of T-cells and thus limit collateral tissue damage in response to infection of microorganisms in this tissue. Best-characterized signal for PD1-inducing ligand 1 (PDL1; also known as B7-H1) is interferon-γ (IFNγ), which is preferably produced by T-cells, helper 1 (TH1)

Immunotherapy of Cancer II: reengineering T cells: CAR T-cells

Doctors collect T cells of the patient. They are placed outside the protein (cytotoxic) cell. This protein is either a T cell receptor or a chimeric receptor antigen (CAR). Then designed T-cells are administered back to the patient. Added protein performs two roles: he directs the T cell directly to the tumor, and on arrival he starts fighting force T cells to attack the cancer cells.

T cells interact through their T cell receptor protein major histocompatibility complex (MHC), which present tumor antigens on the tumor cell surface. T cells may be reinzhinirirovany to represent antibody-like molecules (CAR cells) on their surface. Antibodies are often single chain AB, directed against antigens of tumor cells.


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