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

Division according to the mode of action

 For more information see Cytostatics.

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

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

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