Anticancer therapy

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Biochemical principles of anticancer treatment

Anticancer treatment modalities[edit | edit source]

Local treatment:

Systemic treatment:

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[edit | edit source]

  • 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

Division according to the mode of action[edit | edit source]

Searchtool right.svg For more information see Cytostatics.

Mitosis inhibitors[edit | edit source]

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[edit | edit source]

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

Topoisomerase inhibitors

  • Topoisomerase I inhibitors
  • Topoisomerase II inhibitors
  • 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
  • Alkylating and intercalating agents
  • Bleomycin – glycopeptide ATBs produced by streptomycetes
  • indication: HD, testicular cancer
  • Mitomycin – a product of streptomycetes

Enzyme inhibitors[edit | edit source]

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
  • 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[edit | edit source]

Attempts to stimulate the immune system, to recognise and attack neoplastic cells:

  • cytostatic to cytolytic effect
  • immunogenicity is increased by altering surface molecules
  • indications: renal cell cancer, in hematooncology
  • 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[edit | edit source]

  • 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[edit | edit source]

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

náhled|vpravo|400 px|Aromatase effect

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[edit | edit source]

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
  • 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[edit | edit source]

  • 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
  • formerly in breast cancer
Estrogens – diethylstilbestrol
  • suppression of testosterone production
  • used in prostate cancer
  • 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)[edit | edit source]

  • 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“)[edit | edit source]

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“)[edit | edit source]

  • 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)
  • 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)
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)