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CHEMOTHERAPEUTICS OF MALIGNANT DISEASES
A. Kohút
Carcinogenesis
DNA mutation
• hereditary
• acquired
radiation viruses chemicals drugs
Categories of genetic changes resulting in malignity
a) inactivation of tumor supressor genes:
• mutation• binding to a virus protein• binding to a mutated
cellular protein
b) activation of protooncogenes to oncogenes:
• point mutation
(single nucleotide polymorphisms-SNPs)
• gene amplification• chromosome
translocation• virus interaction
Oncogenes – autonomy of cell growth
Oncogenes interfere with:• mechanisms of proliferation• mechanisms of differentiation
by means of:• production secretion of autocrine
growth factors• receptors for growth factors• cytosolic nuclear signal pathways• transduction systems controling cell cycle
Characteristics of tumour cells
• uncontrolled proliferation
• dedifferentiation loss of function
• invasiveness
• metastatic potential
Therapeutic effect of anticancer drugs
a. The therapeutic effect of anticancer drugs may require total tumor cell kill, which is the of all neoplastic cells.
b. Achievement of a therapeutic effect often involvs drugs that have a narrow therapeutic index (TI).
c. A therapeutic effect is usually achieved by killing activelly growing cells, which are most sensitive to this class of agents.
d. Because normal cells and cancer cells have similar sensitivity to chemotherapeutic agents, adverse effects are mostly seen in normally dividing non-neoplastic cells, sach as:
hair follicles, bone marrow, sperm.e. To minimize the adverse effects and resistance, often is used
combination of several agents with different mechanism of action.
f. Achievement of a therapeutic effect may involve the use of drugs, sometimes sequentially (at specific stages of cell cycle).
„PRODRUGS“ 1. Cyclophosphamide 4-Hydroxyphosphamide (liver) 2. Procarbazíne dacarbazine (liver) 3. Merkaptopurine 6-merkaptopurine ribozophosphate 4. Tioquanín 6-tioquanín-ribózophosphate 5. Fluorouracil 5-fluoro-deoxy- uracil monophosphate 7. Mitomycin (only at the hypoxic tissue of tumors) 8. Doxorubicin idarubicin
SENSITIVITY OF TUMOURS TO CHEMOTHERAPY
• chemosensitive tumours
• intermediary chemosensitive
tumours
• chemoresistant tumours
Chemosensitive tumours
• generally sensitive to several drugs
• combined chemotherapy is prefered
• chemotherapy is always indicated
Intermediary chemosensitive tumours
• complete remission rate about 10%
• high partial response (about 50%)
• combined chemotherapy is slightly more effective
• chemotherapy could be used
(no as first-choice therapy)
Chemoresistant tumours
• low response rate (about 20%)
• complete remission is rare
• chemotherapy has only adjuvant role
• neoadjuvant therapy
Factors influencing chemotherapy response
• fraction of proliferating cells
• cell cycle rate
• synchronisation of cell cycle within tumour
• tumour mass large tumours are relatively less sensitive: 1. a lot of cells in G0 2. penetration of drugs
• kinetics of cell killing cytotoxic drugs kill only a part of cells of certain type
• resistance of tumour cells
Mechanisms of resistance I.• Defect activation
– cyclophosphamide needs metabolic activation – metothrexate needs conversion to MTX-
polyglutamate in cells
• Increased inactivation – sulfhydryl substances - glutathion, metalothionein – scavenge
reactive molecules– aldehyde dehydrogenase – inactivation of cyclophosphamide
• Increased nucleotide levels– can affect the effectiveness of antimetabolites
• Changes in DNA repare repare mechanisms, elimination of cross-links– bleomycine other DNA-interfering drugs
Mechanisms of resistance II.
• Changes in target structure – active enzyme with lower drug affinity:
DFR-metothrexate
• Reduced quantity of target structure amount of topo II: etoposide
• Gene amplification– metothrexate: DFR requires more MTX
to block the activity
Mechanisms of resistance III.
• Decreased accumulation
– Decreased uptake • MTX - protein transporter• melphalan/leucine transport
– Increased efflux • multidrug resistance (MDR):
- most often for natural drugs doxorubicine, etoposide, actinomycine D, vinca alcaloids
- Pgp is normally expressed in some cells, e.g. stem cells in bone marrow
Combination chemotherapy
• tumours have tendency to be resistant to some drug (cell heterogeneity)
• resistance is often required during therapy with only one drug (proliferation of mutated cells)
• several sites of effect are possible with drugs with different side effects
• cummulative biochemical damage appear in cancer cells
MODALITIES OF ANTICANCER CHEMOTHERAPY
1. Intermittent application• period for bone marrow regeneration• period for immunity regeneration
2. Continual therapy• during maintenance therapy (chlorambucil in CLL, busulfan in CML, hormones or
antagonists in prostate or breast carcinoma)
3. Special applications• instilation in malignant secretions (bleomycine, thiotepa) (can be palliative by volume reduction)• intrathecal (metothrexate) (infiltration of CNS in leukemia)
INDIVIDUALISATION OF CANCER THERAPY
Type of tumour:• selection of anticancer drug• combination (or not)
Repeated evaluation of clinical status:• continuation (or not) in agressive therapy
Continual monitoring of bone marrow:• before & during therapy• reduction (or not) of therapeutic regimen
intensity
The use of drugs modifying unwanted side effects:• antiemetics, colony-stimulating factors• increase in therapeutic:toxic ratio
PRACTICAL USE OF ANTICANCER DRUGS
• the doses are expressed in
mg per m2
of body surface
(more precise dose/effect ratio)
Toxic effects of anticancer chemotherapeutics
• myelotoxicity• alopecia • loss of appetite &
weight• nausea & vomitus• taste change• stomatitis,
esophagitis, constipation, diarrhea
• fatigue
• cardiotoxicity• neurotoxicity• lung damage• sterility &
teratogenicity• hepatotoxicity &
nefrotoxicity• ↓ wound healing • ↓ growth (children)• carcinogenicity
ANTICANCER DRUGS
Mechanism of action - cell cycle
• intercalation• blockade of metabolic
steps in DNA synthesis
of enzymes regulating cell cycle
RNA synthesis protein synthesis microtubular
functions
Cell cycle intervals & anticancer drugs interferrence
Anticancer drugs
1. alkylating agents (cyclophosphamide, cisplatin)2. antimetabolites (methotrexate)3. cytotoxic ATB (antracyclines)4. mitosis inhibitors (vincristine, taxans)5. topo inhibitors (topotecan, etoposide) 6. hormones (corticoids, tamoxifen, flutamide)7. enzymes & other drugs (asparaginase,
procarbazine, hydroxyurea)8. PTK inhibitors (imatinib)9. monoclonal antibodies
(rituximab,trastuzumab)
I. Alkylating agents
• cyclophosphamide• platinum derivatives• derivatives of nitrosourea (lomustine,
carmustine)• estramustin• melphalan• chlorambucil• busulphan• dacarbazine
Mechanism of action
• inter- or intra-chain cross-linking
• interference with transcription & replication (S phase & G2 block)
• apoptosis
Alkylating agents
Side effects
• myelosuppresion
• GIT toxicity
• inhibition of gametogenesis (sterility-males)
• secondary malignities (acute leukemias)
Cyclophosphamide(mustard gas)
• frequently used
• also as immunosupressive agent
• P-450 activation
• p.o., i.v, i.m.
• derivative - ifosfamide
Cyclophosphamide
Side effects
• myelosuppression
• GIT toxicity
• hemorrhagic cystitis – acroleine
N-acetylcyst., mesna
Cisplatin, carboplatin
• platinum complex
2 chlorid ions
2 amonium groups
• cross-linking,
DNA denaturation
• solid tumors - testes & ovarial
Cisplatin
Kinetics slow i.v. perfusion
(water soluble)
Side effects • myelosuppression
• GIT toxicity• nephrotoxicity• emetogenity • ototoxicity
• neuropathies
II. Antimetabolites
• Antagonists of folic acid
• Pyrimidine derivatives (thymine, cytosine, uracil)
DNA RNA
• Purine derivatives (adenine, guanine)
Methothrexate(antifolate)
Mechanism of action
• folates – purine nucleotides – thymidilate – DNA
• reduction to FH4
• DHFR - high affinitt for FH4 - key enzyme
• transport of monocarbon groups• uracile methylation to 2-deoxyuridylate
(DUMP) & thymidylate (DTMP)
• DNA synthesis
Methothrexate
Kinetics• low liposolubility• p.o., i.v., i.m., i.t.• folate transport (in the cell)
• polyglutamation (intracellular)
• higher affinity to DHFR as FH2
• FH4 depletion
Side effects• myelosuppression,
GIT, pneumonitis, nephrotoxicity (tubular precipitation - hydratation)
• high doses – followed by folic acid
Fluorouracil (5-FU)(pyrimidine (uracile) derivative)
Mechanism of action• interference with
thymidylate & DNA synthesis
• fluorodeoxyuridine monophosphate formation (FDUMP)
• parenteral application • mainly solid tumors
(GI)
Side effects• GI epithelial damage• myelotoxicity
Cytarabine (pyrimidine (cytidine) derivative)
Mechanism of action
• intracellular phosphorylation
• DNA & RNA incorporation
• DNA polymerase inhibition
• Inhibition of replication & reparation
Kinetics & indications
• s.c. (myelodysplastic syndrome), i.v., i.t.
• AML, CML remission, lymphoma, myelodysplast. sy
Side effects• myelosuppression, GIT,
nausea, vomiting
III. Cytotoxic ATB
• Anthracyclines(daunorubicine, doxorubicine, epirubicine,
idarubicine)
• Bleomycines
Daunorubicine (anthracycline)
Mechanism of action
• intercalating ATB• topo II inhibition
Indications• induction therapy
ALL, AML,
CML blast. trans.
Kinetics• i.v. infusion
• metab. & excretion (mainly liver)
Side effects• myelotoxicity• accumulative cardio-
toxity (free radicals)
• alopecia • local necrosis
(extravascular appl.)
Doxorubicine (anthracycline)
Mechanism of action
• intercalating ATB • inhibition of topo II • much broader
indication spectrum as dau
• Hodgkin, NHL, myeloma, at least all localizations of solid tumors
• i.v. perfusion, intravesically
Side effects• myelotoxicity
• cardiotoxicity (dexrazoxan)
• alopecia, mucositis, necroses in mouth & if applied paravenously
Bleomycines(glycopeptide ATB-radiomimetic)
• Fe ion chelatation, interaction with O2
• superoxide & hydroxyl radicals
• degradation of preformed DNA
• chain fragmentation
• radiomimetic effect
• most effective in G2 & M phase, as well as G0
• testicular tumors & malignant lymphomas
• orofacial tumors, ca vulvae, penis, skin
• i.v., i.m.
Side effects• shivering, fever• lung fibrosis• allergies, mucocutaneous
reactions• low hemat. tox.
IV. Mitosis inhibitors
• Vinca alcaloids(vincristine, vinblastine, vinorelbine)
• Taxans(paclitaxel, docetaxel)
Mechanism of actionInhibition of polymerisation:
colchicin
vinca alcaloids
Tubuline Microtubulus
Stimulation of polymerisation Inhibition of depolymerisation
taxans
Vincristine (vinblastine, vinorelbine)
(mitosis inhibitors)
Mechanism of action• inhibition of tubuline polymerisation • inhibition of mitotic spindle
formation• effective in G2/M phase
Side effects• myelosuppression phagocytosis, chemotaxy of
leukocytes axonal transport in neurons• paresthesies, neuromuscular
abnormalities
Vincristine, vinblastine
Indications
Vincristine• ALL & AML• Hodgkin lymphoma, NHL• multiple myeloma• combination therapy in some solid tumors
Vinblastine• Hodgkin lymphoma, NHL• testicular tumors• choriocarcinoma• Grawitz tumor
Paclitaxel, docetaxel(mitosis inhibitors)
Mechanism of action
• microtubular stabilisation
• final effect like vinca alcaloids
Kinetics• very low water
solubility• only as i.v. perfusion
Paclitaxel, docetaxel
Side effects
• myelosuppression• neurotoxicity• hypersensitivity
(premedication with
steroids & antihistaminics)
Indications
• metastatic tumors (breast)
• progressive ovarial tumors
• NSCLC• Kaposi sarcoma (AIDS)
V. Topoisomerase inhibitors
• topo I inhibitors(topotecan, irinotecan)
• topo II inhibitors(etopozide, tenipozide)
Topotecan (irinotecan)(topo I inhibitors)
Mechanism of action• topo I inhibition• its levels are during
the whole cell cycle
Side effects• diarrhea, reversible
myelosuppression• relatively low toxicity
Indications
• metastatic ovarial tumors in case of first line therapy failure (topotecan)
• colorectal ca in progress (irinotecan)
Etopozide (tenipozide)(topo II inhibitors)
Mechanism of action• Inhibition of
mitochondrial functions & nucleoside transport
• topo II inhibition
Side effects • nausea, vomitus • myelosuppression,
alopecia
Indications • solid tumors
(lung-SCLC, testicular, trophoblast, ovarial, urinary blader)
• malignant lymphoma, acute non-lymphatic leukemia
VI. Hormones
• Glucocorticoids(prednisolone, dexamethasone)
• Antihormones(tamoxifen, flutamid)
Tamoxifen (toremifen)
Mechanism of action• nonsteroidal
antiestrogene
• inhibits estradiol binding to receptors
Indications• p.o. appl. in breast
cancer with positive estrogene receptors
Side effects
• metrorhagies• thrombophlebitis• flush• alopecia• estrogene
endometrial effect
VII. Enzymes & other chemotherapeutics
• Enzyme(asparaginase)
• Other chemotherapeutics(procarbazine, hydroxyurea)
Asparaginase(enzyme)
Mechanism of action, kinetics, indications• cleaves asparagine, useful in malignities
where the cells lost possibility of its synthesis
• i.m., i.v. in ALLSide effects
• weak myelosuppression, GIT toxicity & alopecia
• nausea, vomiting, CNS depression, anaphylaxis, hepatotoxicity
VIII. PTK inhibitors (imatinib mesylate)
Mechanism of action, kinetics, indications• PTK inhibition
phosphate group transport from ATP & phosphorylation of tyrozine residues in substrate proteins
• Inhibition of transduction signals transmission • p.o. appl. in therapy of CML & GIST
Side effects• nausea, vomiting, diarrhea• edema, headache & muscle pain• neutropenia & thrombocytopenia
IX. Monoclonal antibodies (rituximab, trastuzumab)
Rituximab• monoclonal antibody only for i.v. appl. • indicated in lymphoma therapy
Trastuzumab• monoclonal antibody only for i.v. appl. • indicated in HER2 Neu positive breast ca therapy
Side effects• pseudoinfluenza sy.• fever • headache, chest, abdominal, muscle & joint pain• nausea, vomiting, diarrhea & exanthema
Angiogenesis in cancer
Vasculogenesis vs Angiogenesis
Formation of blood vessels from differentiating angioblasts and their organization into a primordial vascular network, consisting of the major blood vessels of the embryo
Formation of vascular sprouts from pre-existing vessels
Vasculogenesis
Agiogenesis
Physiological versus pathological angiogenesis
Physiological angiogenesis
Pathological angiogenesis
Therapeutic goal
Inhibition of angiogenesis Stimulation of angiogenesis
Embryogenesis Female reproductive systemDevelopment of folliclesCorpus luteum formationEmbryo implantation Successful wound healing
Hemangiomas Psoriasis Kaposi's sarcoma Ocular neovascularization Rheumatoid arthritis Endometriosis Atherosclerosis
Tumor growth and metastasis
Myocardial ischemia Peripheral ischemia Cerebral ischemia Wound healing Reconstructive surgery Ulcer healing
Initiation
Promotion
Dormant in situ Cancer
1 kg
1 g
1 mg
1 g
1 ng
Established tumor
Dormant cancer cells regain tumorigenic
potential Suzuki M et al AJP 169: 673-681
Angiogenic switch
Progression of Cancer
Hypoxia crosstalk
Accessory cells
Metasta
sis
Hanahan D & Folkman J. Cell. 86:353, 1996
The balance hypothesis for the angiogenic switch
VEGF family
FGF family
PDGF
TGF family
Angiogenin
Angiopoietin-1/Tie2
TNF-HGF/scatter factor
IGF family
IL-8
Nitric oxide
Prostaglandins
Tissue factor
MMPs
.
.
.
Angiostatin/other plasminogen kringles
Antithrombin (cleaved)
Endostatin
Fibronectin fragments
PEX
16-kDa Prolactin
Prothrombin kringle-2
Maspin
Restin
Vasostatin
IL-1, -4, -10, -12, -18
IFNs
TIMPs
1,25-(OH)2-vitamin D
2-Methoxyestradiol
Angiopoietin-2
EMAP-II
gro-IP-10
.
.
.
McDonald & Choyke Nat Med 2003
Normal Blood Vessels vsTumor Blood Vessels
Bevacizumab
• Recombinant, humanized monoclonal antibody that binds to VEGF-A
• Approved for first-line treatment of Non-Small Cell Lung Cancer in combination with Carboplatin and Paclitaxel
• Adding bevacizumab to chemotherapy results in increased median Progression Free Survival by 33%
Concerns
• Since bevacizumab is expected to inhibit new angiogenic growth, concerns have been raised regarding postoperative wound-healing and bleeding complications in patients who undergo surgery within 1 to 2 months of Bevacizumab therapy
Side efects
• Gastrointestinal (GI) perforation
• Wound healing complication
• Hemorrhage
• Neutropenia
Immunosuppressant drugs
- inhibit interleukin-2 production or action cyclosporin, tacrolimus, sirolimus
- inhibit cytokine gene expression corticosteroids
- inhibit purine and pyrimidine synthesis azathioprine
- block the T cell surface molecules involved in signalling polyclonal and monoclonal antibodies
- act by cytotoxic mechanisms cyclophosphamide, chlorambucil
Usage in therapy:
- autoimmune disease (some forms of haemolytic anaemia, glomerulonephritis…)- prevention /or therapy of transplant rejection (kidneys, bone marrow, heart, liver, etc.)
Hazard: - decreased response to infections- facilitation of emergence of malignant cells
Cyclosporin-a fungal polypeptide with potent immunosuppresive activity
Pharmacokinetics- i.v., oral absorption - hepatic metabolism-metabolites excreted in the bile-accumulation in most tissues at conc. 3 to 4 times that seen in the plasma
Unwanted reactions:
- nephrotoxicity- hepatotoxicity- hypertension
Tacrolimus- a macrolide antibiotic- i.v., orally- metabolized by the liver
Unwanted reactions:- neurotoxicity- GIT upsets, metabolic disturbances (hyperglycaemia) reversible by reducing the dosage
Glucocorticoids
- restrain the clonal proliferation of Th cells through decreasing transcription of the gene for IL-2
- decrease the transcription of many other cytokine genes in both the induction and effector phases of the immune response
Azathioprine
is activated to 6-mercaptopurine (a pure analogue –antimetabolite - that inhibits DNA synthesis)
by a cytotoxic action on dividing cells inhibits clonal proliferation in the induction phase of the immune response
Unwanted reactions: - depression of the bone marrow, - nausea and vomiting
Mycophenolate mofetilA semisynthetic derivative of a fungal antibiotic
bioactivated to mycophenolic acid
Action (fairly selective): - restrains proliferation of both T and B lymphocytes- reduces the production of cytotoxic T cells Kinetics:Well absorbed from the GIT Enterohepatic circulation-inactive glucuronides