Anticancer therapy

Biochemical principles of anticancer treatment

Anticancer treatment modalities
Local treatment:
 * surgery
 * radiotherapy

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

Criteria for choosing the modality and type of medicament:
 * 1) guidelines (international – NCCN, national – blue book, constitutional etc.)
 * 2) specific situation (patient status and age, comorbidities, mobility, profession etc.)
 * 3) economic aspects (centralisation of care for patients treated with expensive drugs etc.)

Chemotherapy

 * developed after World War 1, when nitrogen mustard (alkylating agent) was used for the first time.
 * by interfering with the cell cycle, the neoplastic cells are prevented from another division
 * the most sensitive are the rapidly multiplying cells and cells which have a decreased capacity in their reparative mechanisms.
 * non-specific effect, which lead to the characteristic side effect of the treatment (effecting the physiologically rapidly dividing cells):
 * temporary suppression hematopoiesis (hematopoietic cells of the bone marrow)
 * GIT symptoms (gastrointestinal mucosa)
 * alopecia (cells of the hair follicles) and more

Mitosis inhibitors

 * Vinca-alcaloids („mitotic poisons“) – Vinblastine, Vincristine, Vinorelbine
 * Vinca-alcaloids used today are made synthetically
 * they bind on the β-subunit tubulin and thus disrupt the dynamic growth and degradation of microtubules – microtubules dont polymerise (they depolymerise in increased concentration)
 * indications: breast cancer, lung and more


 * Taxanes – Docetaxel, Paclitaxel
 * diterpenes (chemically)
 * originally come from a tree (pacific yew) (paclitaxel), nowadays they are produced synthetically
 * bind on the β-subunit of polymerised tubulin increasing the affinity of the tubulin units to each other – stabilisation of microtubules of the mitotic spindle – stopping mitosis during the transition from metaphase to anaphase
 * indications: breast cancer, ovary, prostate 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, besides DHFR thymidylate synthase and glycinamide ribonucleotide formyltransferase are also inhibited


 * Purine analogues
 * Pentostatin inhibits adenosine-deaminase
 * thiopurines inhibit the synthedsis and metabolism of purines (Mercaptopurine)


 * Pyrimidine analogues
 * inhibit thymidylát syntázu (5-FU, Capecitabine) – cancers of GIT, breast etc.
 * inhibit DNA-polymerase|
 * inhibit ribonucleotide-reductase (Gemcitabine) – pancreatic cancer
 * inhibit DNA methylation


 * Ribonucleotide-reductase inhibitors
 * Hydroxyurea – used in Myeloproliferative diseases

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


 * Topoisomerase II inhibitors
 * etoposide – lung cancer, testicular cancer and more


 * Topoisomerase II inhibitors with intercalating activity
 * anthracyclines = anthracycline ATB
 * produced by strains of Streptomyces bacteria
 * in addition to inhibiting topoisomerase II, it also acts by intercalating(they are inserted between two strands of DNA)
 * Doxorubicin, Epirubicin – breast, ovarian, hematological cancers

Substances acting by an alkylation or intercalation mechanism
 * Drugs acting by an alkylation mechanism
 * alkylating agents: transfer an alkyl group (CnH2n+1) to the N7 of the guanine imidazole ring
 * cyclophosphamide – hematological malignancies


 * Platinum cytostatics
 * they do not alkylate in the true sense of the word - they do not possess an alkyl group - only a similar effect as alkylating agents
 * they bind on the DNA and form intercalating bonds that prevent replication and reparative processes
 * CDDP (cisplatin), oxaliplatin, CBDCA (carboplatin) – basis of combined chemotherapeutic regimens of many solid tumors (sarcomas, ovarian cancer, lung cancer)


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


 * Alkylating and intercalating agents
 * Bleomycin – glycopeptide ATBs produced by streptomycetes
 * indication: HD, testicular cancer
 * Mitomycin – a product of streptomycetes
 * breast cancer, urinary bladder cancer

Enzyme inhibitors

 * Farnesyltransferase inhibitors – Tipifarnib
 * prevents the attachment of Ras protein on the cell membrane
 * when inhibiting farnesyltransferase, Ras protein (K and N) can also be modified by geranylgeranyltransferase
 * blockage of both pathways leads to strong toxicity of the preparation preventing its use
 * in clinical research phase


 * Cyclin-dependent Kinase inhibitors (CDKi) – Seliciclib
 * preferentially inhibit CDK2, 7 and 9
 * in vitro activation of apoptosis in malignant cells
 * in the phase of clinical trials for the indication in NSCLC and in leukemia


 * Proteasome inhibitors– Bortezomib
 * proteasome inhibitor (inhibits its chymotrypsin-like proteolytic activity)
 * leads to cell cycle arrest by stabilising negative cell cycle regulators (pro-apoptotic proteins aren't degraded, which leads to apoptotic induction)
 * demonstrated activity in multiple myeloma and mantle cell lymphoma


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


 * Unclassified
 * Trabectedin
 * isolated from catfish
 * demonstrated activity for soft tissue sarcomas
 * not fully understood mode of action (apparently reduces the molecular O2 to form superoxide by auto-redox reaction in the vicinity of DNA, leading to irreversible damage)


 * Temsirolimus
 * specific inhibitor of mTOR (mammalian Target Of Rapamycin) kinase, which modifies growth signals
 * excessive activation of mTOR increases the concentration of cyclin D and HIF, leading to stimulation of VEGF production
 * used in renal carcinoma, where mTOR ,usually ,has increased activity


 * Oblimersen
 * blc2 antisense oligonukleotide – blocks the production of BCL2 protein – apoptosis inhibitor
 * in clinical trials phase

Tumor immunotherapy
Attempts to stimulate the immune system, to recognise and attack neoplastic cells:
 * administration of systemic cytokines
 * interferon α
 * cytostatic to cytolytic effect
 * immunogenicity is increased by altering surface molecules
 * indications: renal cell cancer, in hematooncology
 * interleukin 2
 * acts by activating T-lymphocytes
 * indications: renal carcinoma, malignant melanoma


 * administration of an attenuated strain of BCG (Bacillus Calmette-Guérin) in urinary bladder carcinoma – decreased the risk of recurrence after resection
 * adoptive immunotherapy – eg. administration of donor lymphocytes – in clinical trials phase
 * monoclonal antibodies – see biological therapy

Antitumor hormonal therapy

 * antiquity, middle ages  – observations: in castrated individuals there was almost no occurrence of prostate cancer
 * 1896 Beatson first performed oopherectomy in breast cancer preventing the disease progress, which lead to regression of metastatic chest wall involvement
 * the oldest „biological“ (in the sense of targeted) therapy
 * mostly used for malignancies derived from hormone-dependent tissue
 * generally the manipulation of the endocrine system can be performed:
 * 1) exogenous administration of hormones
 * 2) by administering a substance that inhibits the production or activity of endogenous hormones
 * 3) surgical removal of endocrine organs (oopherectomy, adnexectomy)

Hormone synthesis inhibitors
náhled|vpravo|400 px|Aromatase effect
 * Gonadotropin Releasing Hormone (GnRH)
 * physiologically it stimulates the production of LH and FSH
 * administration leads to chemical castration
 * after a period of administration (depot form), increased LH and FSH production leads to down-regulation of LH and FSH receptors in the ovaries or in the testes, resulting in a decrease in testosterone in men and estrogen in women, leading to castration(menopausal) levels
 * paradoxically, there is an increase in secretion before the onset of the effect – there is the need to administer a receptor antagonist
 * goserelin – breast and prostate cancers
 * Aromatase inhibitors (AI)
 * aromatase is an enzyme responsible for the key-step in estrogen biosynthesis – it aromatises androgens to form estrogens
 * AIs competitively and reversibly inhibit aromatase
 * used in post-menopausal women for receptor-positive breast cancer
 * Letrozole, Anastrozole

Antagonists of hormonal receptors

 * Selective modulators of estrogen receptors (SERM)
 * act on estrogen receptors
 * different activity in different tissues – agonistic effect in some tissues – it depends on the co-activation and estrogen receptor conformation
 * Tamoxifen
 * antagonist and agonist (eg. on endometrial mucosa – risk of hyperplasia developing into endometrial cancer)
 * indicated in hormonally positive breast cancer in both pre- and post-menopausal patients
 * biologically active only after being activated in the liver by the enzyme CYP2D6 (various isoforms, some so-called „poor metabolisers“ – amoxifen is not sufficiently effective)


 * fulvestrant
 * on estrogen receptor (ER) antagonist, down-regulates and leads directly to ER degradation
 * in post-menopausal ER+ breast cancer in Tamoxifen failure


 * Antiandrogens
 * antagonists of androgen receptors
 * commonly in combination with GnRH analogues or with surgical castration – the so-called complete androgen blockage
 * treatment for prostate cancer
 * flutamide
 * competes with testosterone DHT for the binding on androgen receptors


 * bicalutamide
 * replaced flutamide because of less side effects
 * binds on the androgen receptor and accelerates its degradation

Other

 * some hormone receptor agonists may have anti-proliferative to cytotoxic effects
 * Gestagens – megestrol
 * not fully understood principle
 * a direct effect on tumor cells and an indirect endocrine effect are expected
 * 3rd line of hormonal therapy in breast, endometrial and prostate cancers
 * Androgens
 * formerly in breast cancer
 * Estrogens – diethylstilbestrol
 * suppression of testosterone production
 * used in prostate cancer
 * Corticosteroids
 * not fully understood mechanism – possibly reduce uridine incorporation in RNA and with this RNA-polymerase effectivity, which leads to the reduced synthesis of RNA and proteins
 * part of chemotherapeutic regimens or in monotherapy for hematological malignancies
 * CLL, multiple myeloma, lymphoma
 * prednisone, dexamethasone
 * Somatostatin analogues
 * synthetic analogues of peptide hormone somatostatin
 * somatostatin inhibits the activity of some hormones adenohypophysis (GH, FSH) and production of peptide hormones in the GIT (gastrin, motilin, VIP, GIP etc.), reducing GIT secretion and motility
 * used in biologically active neuroendocrine tumors – VIPoma, gastrinoma, insulinoma
 * indicated in carcinoid tumor with carcinoid syndrome
 * radioactive octreotide is also used in octreoscan
 * octreotide (Sandostatin)

Biological therapy (Targeted Therapy)

 * blocks the growth of neoplastic cells by affecting specific molecules needed in the process of carcinogenesis, metastasis and cell growth (difference: chemotherapy „attacks“ all the rapidly dividing cells)
 * mostly the whole spectrum of rather non-specific side effects of X chemotherapy

Monoclonal antibodies („-mab“)

 * Monoclonal antibodies against tyrosine kinase receptors
 * Cetuximab (Erbitux)
 * chimeric (mice/human) monoclonal antibody (IgG1) against EGFR
 * expressing EGFR, KRAS wildtype (non-mutated generalised colorectal carcinoma; mCRC) and in head and neck tumors


 * Trastuzumab (Herceptin)
 * human monoclonal antibody against ErbB2 (HER2/neu)
 * mechanism of action:
 * down-regulates HER2/neu, which can't dimerize and thus can't initiate signal transduction of PI3/Akt and MAPK (P27Kip1 is not phosphorylated, penetrates the nucleus and may inhibit cdk2 activity)
 * inhibit angiogenesis
 * „marks“ tumor cells for the immune system
 * used in breast cancer with over-expression of her2/neu
 * in the Czech Republic, over-expression must be proven both by immunohistochemistry (IHC +++), and by fluorescence in situ hybridisation (FISH)
 * main side effect is cardiotoxicity


 * Monoclonal antibody against other structures in solid tumors
 * Bevacizumab (Avastin)
 * humanised monoclonal antibody against VEGF
 * the first clinically used inhibitor of angiogenesis
 * in combination with chemotherapy in mCRC
 * clinical trials are underway for other diagnoses without generalization
 * side effects due to angiogenesis inhibition: hypertension – risk of Stroke, ledvin damage


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


 * Monoclonal antibodies against other structures in leukemias and lymphomas
 * Rituximab (MabThera)
 * a chimeric monoclonal antibody against CD20 found on mature B-lymphocytes (not present on plasma cells)
 * mechanism of action not fully understood (possibly a combination of several additive mechanisms)
 * used in B-lymphoma, leukemia and some autoimmune diseases


 * Alemtuzumab
 * antibody against CD52 found on mature lymphocytes, but not on stem cells
 * 2nd line of therapy for B-CLL, T-lymhomas


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

Low molecular weight inhibitors of kinases („-inib“)

 * inhibit specific one or more protein kinases
 * can be categorised according to the AMK, whose phosphorylation they inhibit
 * most common inhibitors of tyrosine kinases
 * usually „small molecules“ → penetrate biological barriers X Ig


 * Receptor Tyrosine Kinase Family Inhibitors – ERB (EGFR)
 * HER1/EGFR
 * Erlotinib (Tarceva)
 * reversibly binds to ATP binding site – preventing auto-phosphorylation and thus signal initiation
 * indications: NSCLC (non-small cell lung cancer) after failure of 1st line of treatment
 * with gemcitabine in generalised pancreatic cancer
 * Gefitinib
 * similar to Erlotinib; indicated in NSCLC


 * HER2/neu
 * Lapatinib (Tyverb)
 * a dual inhibitor – binds on the binding site for ATP receptor tyrosine kinase in both EGFR and Her2/neu, preventing auto-phosphorylation and signal initiation
 * able to act against the so-called cancer stem cells (CSC) – they posses properties of physiological stem cells – eg. they produce all type of cells in the tumor, also, it is believed that they are responsible for relapse and metastasis of the tumor
 * indicated in the therapy of Her2/neu positive breast cancer
 * Neratinib


 * Receptor tyrosine kinase inhibitors class III
 * Sunitinib (Sutent)
 * inhibits several receptor tyrosine (PDGFR, VEGFR, c KIT (CD117), RET etc.)
 * indicated in renal cell carcinoma metastasis and in imatinib-resistant gastrointestinal sstromal tumor (GIST)


 * Sorafenib (Nexavar)
 * inhibits several receptor tyrosine
 * the only one that blocks Raf/Mek/Erk (MAP-kinase) signalling pathways
 * in advanced or metastasized renal cell carcinoma and hepatocellular carcinoma


 * Receptor tyrosine kinase inhibitors – VEGFR
 * Vandetanib – in clinical trials for SCLC
 * Semaxanib – in clinical trials for CRC
 * Cediranib – in clinical trials for RCC, SCLC
 * Axitinib – in clinical trials for pro RCC
 * Sunitinib
 * Sorafenib
 * Toceranib – used in the therapy of mastocytoma
 * Regorafenib


 * Non-receptor tyrosine kinase inhibitors
 * Imatinib (Glivec)
 * used in GIST, CML and Dermatofibrosarcoma protuberans
 * CML with t(9;22) – Philadelphia chromosome – through translocation a fusion protein bcr-abl occurs, a constantly active tyrosine kinase, whose activity is reduced by imatinib, but it also binds on c-kit and PDGFR
 * binds on ATP binding site

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