Antitumor therapy

Biochemical principles of antitumor treatment

Antitumor Treatment Modalities
Local treatment:
 * surgery
 * radiotherapy

Systemic therapy:
 * chemotherapy
 * immunotherapy
 * hormonal treatment
 * biological therapy

Criteria for the choice of modality and type of drug:
 * 1) guidelines (international - NCCN, national - blue book, constitutional, etc.)
 * 2) specific situation (condition and age of the patient, comorbidities, mobility, profession, etc.)
 * 3) economic aspects (centralization of care for patients treated with expensive drugs, etc.)

Chemotherapy

 * development after World War I, when nitrogen mustard mustard (alkylating agent) was used for the first time
 * by interfering with the cell cycle tumor cells prevent their further division
 * the most sensitive are rapidly proliferating cells and cells that have a reduced ability to repair DNA errors
 * acts non-specifically, which leads to the characteristic undesired effects of the treatment (effect on physiologically rapidly dividing cells):
 * temporary suppression of blood formation (hematopoietic cells of the bone marrow)
 * GIT problems (mucosal cells of the alimentary canal)
 * alopecia (hair follicle cells) and others

Mitosis inhibitors

 * Vinca alkaloids ("mitotic poisons") – Vinblastine, Vincristine, Vinorelbine
 * alkaloids of periwinkle, synthetically produced in use today
 * they bind to the β-subunit of tubulin and thus disrupt the dynamics of growth and degradation of microtubules - there is no polymerization of microtubules (they depolymerize directly at increased concentrations)
 * Indications: breast cancer, lung and others


 * Taxanes - Docetaxel, Paclitaxel
 * chemically diterpenes
 * originally from Pacific yew (paclitaxel), now produced synthetically
 * by binding to the β-unit of polymerized tubulin, they increase the affinity of tubulin units to each other - stabilization of the microtubules of the dividing spindle - stopping of mitosis during the transition from metaphase to anaphase
 * indication: breast cancer, ovarian cancer, prostate cancer etc.

Substances interfering with DNA replication

 * DNA precursors
 * Antifolates - prevent the normal function of folic acid in the body
 * Methotrexate – competitively and irreversibly inhibits DHFR (dihydrofolate reductase) – binds 1000 times more easily, part of many therapeutic regimens
 * Pemetrexed – structurally similar to folic acid, in addition to DHFR it also inhibits thymidylate synthase and glycinamide ribonucleotide formyltransferase


 * Purine analogs
 * Pentostatin inhibits adenosine deaminase
 * thiopurines inhibit the synthesis and metabolism of purines (Mercaptopurine)


 * Pyrimidine analogs
 * inhibit thymidylate synthase (5-FU, Capecitabine) – cancers of the GIT, breast etc.
 * inhibit DNA-polymerase
 * inhibit ribonucleotide reductases (Gemcitabine) – pancreatic cancer
 * inhibit DNA methylation


 * Ribonucleotide reductase inhibitors
 * Hydroxyurea – in myeloproliferative diseases

Topoisomerase Inhibitors'
 * Topoisomerase I inhibitors
 * topotecan – ovarian cancer + SCLC
 * irinotecan – colon cancer


 * Topoisomerase II inhibitors
 * etoposide - lung cancer, testicular tumors and others


 * Topoisomerase II inhibitors with intercalation activity
 * anthracyclines' = anthracycline ATB
 * produced by strains of bacteria Streptomyces
 * in addition to inhibiting topoisomerase II, it also acts as an intercalator (they are inserted between two DNA strands)
 * Doxorubicin, Epirubicin – cancer of the breast, ovaries, hematological malignancies

Substances acting by an alkylating or intercalating mechanism'
 * Drugs acting through an alkylating mechanism
 * alkylating agents: transferring an alkyl group (CnH2n+1) to N7 of the imidazole ring guanineu
 * cyclophosphamide – hematological malignancies


 * Platinum cytostatics
 * do not alkylate in the true sense of the word - they do not have an alkyl group - only a similar effect to alkylating agents
 * bind with DNA to form intercalation bonds that prevent replication and repair processes
 * CDDP (cisplatin), oxaliplatin, CBDCA (carboplatin) – the basis of combined chemotherapy regimens for many solid tumors (sarcomas, ovarian cancer, lung cancer)


 * Non-classical alkylating agents
 * Dacarbazine – malignant melanoma, hematological malignancies
 * Temozolomide – glioblastoma G IV


 * Alkylating and intercalating substances
 * Bleomycin – glycopeptide ATB produced by ``streptomycetes''
 * indication: HD, testicular tumors
 * Mitomycin – a "streptomycete" product
 * breast cancer, bladder cancer

Enzyme inhibitors

 * Inhibitors of farnesyl transferase – Tipifarnib
 * prevents attachment of the Ras protein to the cell membrane
 * when farnesyltransferase is inhibited, the Ras protein (K and N) can also be modified by geranylgeranyltransferase
 * blocking of both pathways leads to strong toxicity of the preparation, making its use impossible
 * in the clinical research phase


 * Inhibitors of cyclin-dependent kinases (CDKi) – Seliciclib
 * preferentially inhibits CDK2, 7 and 9
 * in vitro activates apoptosis of malignant cells
 * in the phase of clinical trials in the indication NSCLC and in leukemias


 * proteasome inhibitors – Bortezomib
 * proteasome inhibitor (inhibits its chymotrypsin-like proteolytic activity)
 * leads to cell cycle arrest by stabilizing negative cell cycle regulators (proapoptotic proteins are not degraded, leading to induction of apoptosis)
 * proven efficacy in Multiple Myeloma and Mantle Cell Lymphoma

PARP inhibitors (Poly ADP Ribose Polymerase inhibitors)
 * PARP, together with the product of the BRCA 1/2 genes, is involved in the repair of 1 and 2 DNA strand breaks
 * more effective in tumors with an inactivating mutation in the BRCA 1/2 gene
 * Olaparib – promising results in hereditary breast cancer, ovarian cancer and prostate cancer


 * Uncategorized
 * Trabectidine
 * isolated from catfish
 * efficacy demonstrated for soft tissue sarcomas
 * mechanism of action not fully clarified (apparently reduces molecular O2 to form superoxide by an auto-redox process near DNA, which leads to irreversible damage)


 * Tensirolimus
 * a specific mTOR (mammalian Target Of Rapamycin) kinase inhibitor that modifies pro-growth signals
 * with excessive activation of mTOR, there is an increase in the concentration of cyclin D and HIF, which leads to the stimulation of VEGF production
 * in renal carcinoma, where mTOR often has increased activity


 * Oblimersen
 * blc2 antisense oligonucleotide - blocks the production of the BCL2 protein - an inhibitor of apoptosis
 * in the clinical research phase

Antitumor immunotherapy
Trying to stimulate the immune system to recognize and destroy tumor cells:
 * by administering systemic cytokines
 * interferon α
 * cytostatic to cytolytic effect
 * changes in surface molecules lead to an increase in immunogenicity
 * indication: generalized kidney cancer, in hemato-oncology
 * interleukin 2
 * has an activating effect on T-lymphocytes
 * indication: kidney cancer, malignant melanoma


 * administering an attenuated strain of BCG (Bacillus Calmette-Guérin) in bladder cancer - reduces the risk of disease recurrence after resection
 * adoptive immunotherapy - eg administration of donor lymphocytes - in the clinical research phase
 * monoclonal antibodies' - see biological therapy

Antitumor hormone therapy

 * ancient times, middle ages' - observation: castrates had almost no prostate cancers
 * 1896 Beatson was the first to perform ovariectomy for breast cancer to stop the progression of the disease, leading to regression of metastatic involvement of the chest wall
 * the oldest "biological" in the sense of targeted therapy
 * mostly used for malignancies derived from hormone-dependent tissue
 * in general, manipulation of the endocrine system can do:
 * 1) by exogenous administration of hormone'
 * 2) by administering a substance that 'inhibits the production or activity of endogenous hormones
 * 3) 'surgical removal of endocrine organs (ovariectomy, adnexectomy)

Inhibition of hormone synthesis

 * Gonadotropin Releasing Hormone (GnRH)
 * stimulates the production of LH and FSH in the body
 * administration leads to chemical castration
 * after a certain period of administration (depot form) the increased production of LH and FSH leads to the down-regulation of receptors for LH and FSH in the ovaries or testes, which results in a decrease in testosterone in men and estrogens in women to the castration (menopausal) level
 * before the onset of the effect, there will paradoxically be an increase in secretion - the need to administer a receptor antagonist
 * goserelin – breast and prostate cancer
 * Aromatase inhibitors (AIs)
 * aromatase (AR) is an enzyme responsible for a key step in estrogen biosynthesis – it aromatizes androgens to form estrogens
 * AIs competitively and reversibly inhibit ARs
 * are used in postmenopausal women with receptor-positive breast cancers
 * letrozole, anastrozole

Hormone receptor antagonists

 * Selective Estrogen Receptor Modulators (SERMs)
 * acts on the estrogen receptor
 * different activity in different tissues - agonistic effects in some tissues - depends on coactivators and conformation of estrogen receptor
 * tamoxifen
 * both antagonist and agonist (e.g. on the endometrial mucosa – risk of hyperplasia up to endometrial cancer)
 * indicated for hormone-positive breast cancers in pre- and postmenopausal patients
 * biologically active only after activation in the liver parenchyma by the enzyme CYP2D6 (various isoforms, some so-called "bad metabolizers" - tamoxifen is then not effective enough)


 * fulvestrant
 * only estrogen receptor (ER) antagonist, down-regulates and leads directly to ER degradation
 * in postmenopausal ER+ ca breasts with tamoxifen failure


 * Antiandrogens
 * androgen receptor antagonists
 * often in combination with GnRH analogues or with surgical castration – so-called total androgen blockade
 * prostate cancer treatment
 * flutamide
 * competes with testosterone and DHT for binding to the androgen receptor


 * bicalutamide
 * replaced flutamide for less intensity of side effects
 * binds to the androgen receptor and accelerates its degradation

Others
Androgens
 * some hormone receptor agonists can have an antiproliferative or cytotoxic effect
 * Progestogens – megestrol
 * the principle is not fully clarified
 * a direct effect on tumor cells and an indirect endocrine effect are assumed
 * III. line of hormone therapy ca mammy, endometrium and prostate
 * previously at ca mom's
 * Estrogens - diethylstilbestrol
 * suppression of testosterone production
 * in prostate cancer
 * Corticosteroids
 * the mechanism is not fully understood - they probably reduce the incorporation of uridine into RNA and thereby the effectiveness of RNA polymerase, which ultimately leads to a reduction in RNA and protein synthesis
 * part of chemotherapy regimens or in monotherapy for hemato-oncological malignancies
 * CLL, multiple myeloma, lymphomas
 * prednisone, dexamethasone
 * Somatostatin analogs
 * synthetic analogues of the peptide hormone somatostatin.
 * somatostatin inhibits the activity of some adenohypophysis hormones (GH, FSH) and the production of GIT peptide hormones (gastrinu, motilin u, VIP, GIP etc.), thereby reducing GIT secretion and motility
 * used for biologically active neuroendocrine tumors – VIPoma, gastrinoma, insulinoma
 * indicated in carcinoids with carcinoid syndrome
 * radioactive octreotide is also used in octreoscan
 * octreotide (Sandostatin)

Biological treatment (targeted therapy)

 * blocks the growth of tumor cells by affecting specific molecules important in the process of carcinogenesis, metastasis and cell growth (difference: classical chemotherapy "attacks" all rapidly dividing cells)
 * usually the whole spectrum of rather non-specific side effects of X chemotherapy

Monoclonal antibodies ("-mab")

 * Monoclonal antibodies against tyrosine kinase receptors
 * Cetuximab (Erbitux)
 * chimeric (mouse/human) monoclonal antibody (IgG1) against EGFR
 * in EGFR expressing, KRAS wildtype (unmutated generalized colorectal carcinomas; mCRC) and in head and neck carcinoma


 * Trastuzumab (Herceptin)
 * human monoclonal antibody against ErbB2 (HER2/neu)
 * mechanisms of action:
 * downregulates HER2/neu, which cannot dimerize and thus does not initiate the PI3/Akt and MAPK signaling pathway (P27Kip1 is not phosphorylated, enters the nucleus and can inhibit cdk2 activity)
 * inhibits angiogenesis
 * "marks" tumor cells for the immune system
 * in breast cancer with her2/neu overexpression
 * in the Czech Republic, overexpression must be proven both by immunohistochemistry (IHC +++) and by fluorescence in situ hybridization (FISH)
 * the main adverse effect is cardiotoxicity


 * Monoclonal antibodies against other structures in solid tumors
 * Bevacizumab (Avastin)
 * humanized monoclonal antibody against VEGF
 * the first clinically used angiogenesis inhibitor
 * in combination with chemotherapy in mCRC
 * clinical studies for other diagnoses are ongoing even without generalization
 * side effects from inhibition of angiogenesis: hypertension - risk of CMP, kidney damage


 * Catumaxomab
 * binds EpCAM (epithelial cell adhesion molecule) to tumor cells with one arm and with the other T-lymphocyte and another immunocompetent cell with an Fc fragment - triggers an immune reaction
 * used in the therapy of malignant ascites


 * Monoclonal antibodies against other structures in leukemias and lymphomas
 * Rituximab (MabThera)
 * chimeric monoclonal antibody against CD20 protein found on maturing B-lymphocytes (no longer on plasma cells)
 * mechanism of action not entirely clear (probably a combination of several additive mechanisms)
 * treatment of B-lymphomas, leukemias and some autoimmune diseases


 * Alemtuzumab
 * antibody to CD52 is found on mature lymphocytes but not on stem cells
 * second-line therapy in B-CLL, T-lymphomas


 * Gemtuzumab
 * antibody against CD33, expressed on most leukemic blasts
 * in AML

Small molecule inhibitors of kinases ("-inib")

 * inhibit specifically one or more protein kinases
 * can be categorized according to the AMK whose phosphorylation they inhibit
 * most often tyrosine kinase inhibitors
 * mostly "small molecules" → penetrate biological barriers well X Ig


 * Inhibitors of the receptor tyrosine kinase family - ERB (EGFR)
 * HER1/EGFR'
 * Erlotinib (Tarceva)
 * binds reversibly to the binding site for ATP – prevents autophosphorylation and thus signal initiation
 * indication: NSCLC (non-small cell lung cancer) after failure of at least 1 line of CHT
 * with gemcitabine in generalized pancreatic cancer
 * Gefitinib
 * similar to Erlotinib; indicated in NSCLC


 * HER2/neu
 * Lapatinib (Tyverb)
 * is a dual inhibitor – it binds to the binding site for ATP receptor tyrosine kinases in both EGFR and Her2/neu and thus prevents autophosphorylation and signal initiation
 * able to act against so-called tumor stem cells (cancer stem cells, CSC) – they have the properties of normal stem cells – e.g. produce all types of cells in the tumor, it is assumed that they are responsible for relapses and metastases
 * indicated for the therapy of Her2/neu overexpressed breast Ca
 * Neratinib


 * Inhibitors of receptor tyrosine kinases of class III
 * Sunitinib (Sutent)
 * inhibits several receptor tyrosine kinases (PDGFR, VEGFR, c KIT (CD117), RET etc.)
 * indicated in metastatic renal cell carcinoma and in imitanib-resistant gastrointestinal stromal ttumors (GIST )


 * Sorafenib (Nexavar)
 * inhibits several receptor tyrosine kinases
 * is unique in blocking the Raf/Mek/Erk (MAP-kinase) signaling pathway
 * in advanced or metastatic renal cancer and hepatocellular carcinoma


 * Inhibitors of receptor tyrosine kinases - VEGFR
 * Vandetanib - in clinical trials for SCLC
 * Semaxanib - in the phase of clinical trials for CRC
 * Cediranib - in the phase of clinical trials for RCC, SCLC
 * ''Axitinib' - in the phase of clinical trials for RCC
 * Sunitinib
 * Sorafenib
 * Toceranib - used for therapy mastocytomas
 * Regorafenib


 * Inhibitors of non-receptor tyrosine kinases
 * Imatinib (Glivec)
 * in GIST, CML and dermatofibrosarcoma protuberans
 * CML with t(9;22) - Philadelphia chromosome - translocation produces a fusion protein bcr-abl, which is a constantly active tyrosine kinase whose activity is reduced by imatinib, but also binds to c-kit and PDGFR
 * binds to the ATP binding site