Anticancer drugs Cancer epidemiology - incidence and mortality in the Czech Republic 0 20 40 60 80 100 120 140 Početna100000žen Rok ZN prsu (C50) u žen 90 80 70 60 50 40 30 20 10 0 Početna100000osob Rok ZN kolorekta (C18-C21) 0 10 20 30 40 50 60 70 Početna100000osob Rok ZN plic (C34) 0 20 40 60 80 100 120 Početna100000mužů Rok ZN prostaty (C61) 0 5 10 15 20 25 30 Početna100000osob Rok ZN ledviny (C64) 20 18 16 14 12 10 8 6 4 2 0 Početna100000osob Rok ZN slinivky břišní (C25) incidence mortalita Breast Ca Colorectal Ca NSCLC Prostatic Ca Renal ca Pancreatic Ca Czech Cancer Care in Numbers 2015 Complex Cancer Treatment — Surgery — Radiotherapy — Pharmacoterapy — Psychotherapy, physiotherapy, nutrition care Pharmacotherapy —cytostatic agents ‒classification according to the mechanism of action —endocrine (hormonal) therapy —targeted therapy ‒monoclonal antibodies targeting extracellular part of receptors ‒tyrosine kinase inhibitors / intracellular signaling cascades inhibitors —pain management, supportive care —route of administration: —parenterally (i.v. bolus, infusion, intrathecally, intravesically…) —orally —posology: dose in mg/m2 or mg/kg —monotherapy and combination regimens —repeated administration in cycles pause = patient‘s recovery, prevention of severe AE + „waking“ dormant cells in G0 phase Cytostatic drugs Different efficacy according to the cell cycle phase: —Cell cycle non-specific cytostatics (e.g., busulfan) —Cell cycle specific cytostatics: −Phase-nonspecific (e.g., some of alkylating agents) −Phase-specific (e.g., antimetabolites, taxanes) http://csls-text3.c.u-tokyo.ac.jp/active/13_01.html Cytostatic drugs Cytostatics according to their MoA 1. Drugs that damage the structure of DNA a) Alkylating agents b) Platinum derivatives c) Intercalating agents d) Bleomycin 2. Drugs that inhibit key enzymes of DNA metabolism a) Antimetabolites: i. Purine analogues ii. Pyrimidine analogues iii.Folic acid analogues iv.Hydroxyurea b) Topoisomerase inhibitors: i. Inhibitors of topoisomerase I – camptothecins ii. Inhibitors of topoisomerase II – podophyllotoxins 3. Drugs that alter microtubules a) Inhibitors of tubulin polymerization – Vinca alkaloids b) Inhibitors of tubulin depolymerization – taxanes 4. Others a) Drugs that inhibit protein synthesis – L-asparaginase Drug groups overview 1. Drugs that damage the structure of DNA a) Alkylating agents b) Platinum derivatives c) Intercalating agents d) Bleomycin 2. Drugs that inhibit key enzymes of DNA metabolism a) Antimetabolites: i. Purine analogues ii. Pyrimidine analogues iii.Folic acid analogues iv.Hydroxyurea b) Topoisomerase inhibitors: i. Inhibitors of topoisomerase I – camptothecins ii. Inhibitors of topoisomerase II – podophyllotoxins 3. Drugs that alter microtubules a) Inhibitors of tubulin polymerization – Vinca alkaloids b) Inhibitors of tubulin depolymerization – taxanes 4. Others a) Drugs that inhibit protein synthesis – L-asparaginase Cytostatics according to their MoA A C T G syntesis THF DHF DNA structure alkylating agents 1a) Alkylating agents • MoA: transfer of the alkyl group on nitrogen in nucleobases, covalent bond between two guanines of one or two DNA strands – Inhibition of replication, cell cycle arrest • 50s: first derivatives of sulphur mustard in the clinical practice • AE – typical toxicity: secondary malignancies – hematological 1a) Alkylating agents ALKYLATING AGENTS Nitrosourea derivatives: CYCLOPHOSPHAMIDE LOMUSTINE MITOMYCIN CBUSULFANTEMOZOLOMIDE DACARBAZINE IFOSFAMIDECHLORAMBUCIL MELPHALANE CARMUSTINE 1a) Alkylating agents – main drugs Melphalane • i.v., p.o. administration • treatment of hematological malignancies and solid tumors Cyclophosphamide • i.v., p.o. administration • prodrugs → CYP450 → cytotoxic metabolites • AE: urotoxicity, emetogenity • low doses – immunosuppressant • hematological malignancies and solid tumors Lomustine • p.o. administration • lipophilic, crosses BBB → treatment of brain tumors 1a) Alkylating agents Temozolomide – 100% bioavailability after oral administration – crosses BBB → treatment of brain tumors Busulfan – i.v., p.o. administration – bone marrow transplantation – treatment of hematological malignancies 1a) Alkylating agents A C T G syntesis THF DHF DNA structure platinum derivatives 1b) platinum derivates • MoA: binding on DNA, cross-linking of DNA strands, inhibition of topoisomerases • AE – most important: emetogenity, nephrotoxicity – AE are dose-dependent – prevention of nephrotoxicity: i.v. hydration, forced diuresis • cisplatin – high nephrotoxicity – treatment of solid tumors • others: – carboplatin – oxaliplatin – typical neurotoxicity 1b) platinum derivates A C T G syntesis THF DHF DNA structure intercalating agents 1c) intercalating agents Anthracyclines • MoA: intercalation = insertion between base pairs, binding of DNA strands • AE – typical toxicity: acute and chronic cardiotoxicity • cardioprotective cumulative dose = restraint of therapy (e.g., doxorubicin 550 mg/m2) • i.v., intravesical administration • doxorubicin – treatment of hematological malignancies and solid tumors – modern dosage form (PEGylated liposomes) – higher cumulative dose (860 mg/m2) • others: epirubicin… 1c) intercalating agents – MoA: intercalation between base pairs + inhibition of thymine incorporation → breaks → DNA fragmentation („radiomimetic“ effect) – i.v. administration – treatment of solid tumors – typical AE: fever, hyperkeratosis and hyperpigmentation of skin (flagellate = whip-like) – risk of anaphylactic reaction 1d) bleomycin 1. Drugs that damage the structure of DNA a) Alkylating agents b) Platinum derivatives c) Intercalating agents d) Bleomycin 2. Drugs that inhibit key enzymes of DNA metabolism a) Antimetabolites: i. Purine analogues ii. Pyrimidine analogues iii.Folic acid analogues iv.Hydroxyurea b) Topoisomerase inhibitors: i. Inhibitors of topoisomerase I – camptothecins ii. Inhibitors of topoisomerase II – podophyllotoxins 3. Drugs that alter microtubules a) Inhibitors of tubulin polymerization – Vinca alkaloids b) Inhibitors of tubulin depolymerization – taxanes 4. Others a) Drugs that inhibit protein synthesis – L-asparaginase Cytostatics according to their MoA A C T G syntesis THF DHF metabolism of nucleic acids antimetabolites 2a. antimetabolites - MoA: false substrates = affinity to target structure, loss of endogenous effect → blockade of nucleic acid synthesis, inhibition of nucleotides metabolism enzymes, production of non-sense DNA sequences - prodrugs: intracellular activation mostly by phosphorylation a) purine analogues – 6-mercaptopurine, azathioprine, fludarabine… b) pyrimidine analogues – fluorouracil, capecitabine, gemcitabine… c) folic acid analogues – methotrexate, pemetrexed… 2a. antimetabolites 6-Mercaptopurin • MoA: inhibition of purine nucleobases biosynthesis de novo, inhibition of mutual conversion of purine nucleotides • thiopurin methyltransferase (TPMT): MP → MeMP – genetic polymorphism – ↑toxicity / ↓efficacy – available pharmacogenetic testing of TPMT • p.o. administration, treatment of hematologic malignancies • azathioprine – prodrug of MP, immunosuppressant inactive 2a. Antimetabolites – i/ purine analogs 5-Fluorouracil • MoA: incorporation to RNA + inhibition of thymidylate synthetase • combined chemotherapeutic regimens of solid cancers (i.v.) • AE – typical toxicity: GIT toxicity (mucositis) • biochemical modulation of effect: leucovorin (folinic acid) enhances binding on thymidylate synthetase, i.v. administered before FU – „FUFA“ regimen = colorectal carcinoma • capecitabine – prodrug 2a. Antimetabolites – ii/ pyrimidines analogs Methotrexate - MoA: inhibition of dihydrofolate reductase, thymidylate synthetase and other enzymes - i.v., intrathecal administration, p.o. - leucovorin (folinic acid) – „rescue therapy“, antidote forces free MTX out of healthy cells ; in cancer cells, polyglutamylation is more intensive → more MTXPG → MTXPG cannot be forced out TDM – calculation of time interval from MTX administration, frequently in pediatric patients, less frequent in adults - AE – typical toxicity: nephrotoxicity – precipitation (acute renal failure) prevention: hydration, urine alkalinization (pH 7–7,5) pneumotoxicity - low-dose MTX = immunosuppressant (p.o.) - high-dose MTX = hematological malignancies 2a. Antimetabolites – iii/ folic acid analogs 1. Drugs that damage the structure of DNA a) Alkylating agents b) Platinum derivatives c) Intercalating agents d) Bleomycin 2. Drugs that inhibit key enzymes of DNA metabolism a) Antimetabolites: i. Purine analogues ii. Pyrimidine analogues iii.Folic acid analogues iv.Hydroxyurea b) Topoisomerase inhibitors: i. Inhibitors of topoisomerase I – camptothecins ii. Inhibitors of topoisomerase II – podophyllotoxins 3. Drugs that alter microtubules a) Inhibitors of tubulin polymerization – Vinca alkaloids b) Inhibitors of tubulin depolymerization – taxanes 4. Others a) Drugs that inhibit protein synthesis – L-asparaginase Cytostatics according to their MoA A C T G syntesis THF DHF DNA replication topoisomerase inhibitors 2b. Topoisomerase inhibitors Topoisomerase I inhibitors – camptothecins - plant-derived drugs – identification in bark of the tree Camptotheca acuminata - derivatives: irinotecan, topotecan – treatment of solid tumors Topoisomerase II inhibitors – podophyllotoxins - plant-derived drugs – identification in Podophyllum peltatum - derivatives: etoposide, teniposide – treatment of solid tumors (etoposide) and hematological malignancies (teniposid) 2b. Topoisomerase inhibitors ETOPOSIDE 1. Drugs that damage the structure of DNA a) Alkylating agents b) Platinum derivatives c) Intercalating agents d) Bleomycin 2. Drugs that inhibit key enzymes of DNA metabolism a) Antimetabolites: i. Purine analogues ii. Pyrimidine analogues iii.Folic acid analogues iv.Hydroxyurea b) Topoisomerase inhibitors: i. Inhibitors of topoisomerase I – camptothecins ii. Inhibitors of topoisomerase II – podophyllotoxins 3. Drugs that alter microtubules a) Inhibitors of tubulin polymerization – Vinca alkaloids b) Inhibitors of tubulin depolymerization – taxanes 4. Others a) Drugs that inhibit protein synthesis – L-asparaginase Cytostatics according to their MoA A C T G syntesis THF DHF tubulin Vinca alkaloids and taxanes 3. Tubulin alterating cytostatics - ant-derived drugs - MoA: inhibition of tubuline dimers polymerization inhibition of mitotic spindle formation, depolymerization prevails - i.v. administration, some for p.o. (vinorelbine) - treatment of hematological malignancies and solid tumors - AE – typical toxicity: peripheral neuropathy - original alkaloids: vincristine, vinblastine - semisynthetic derivatives: vinorelbine, vindesin, vinflunine increased affinity to mitotic spindle tubulin, ↓AE 3a. Vinca alkaloids VINBLASTINE • identification: lesser periwinkle (Vinca minor) • isolation: Cataranthus roseus Vinca alkaloids - plant-based drugs - MoA: inhibition of tubulin depolymerization - i.v. administration – treatment of solid tumors - AE – typical toxicity: neurotoxicity - paclitaxel, docetaxel, cabazitaxel - modern dosage form: paclitaxel conjugated with albumine nanoparticles - transporter protein for albumine in cancer cells = better distribution from circulation into the tissues – ↓toxicity, ↑efficacy 3b. taxanes PACLITAXEL • identification and isolation: Taxus brevifolia (Pacific yew) a Taxus baccata (European yew) Taxanes - monotherapy - combination regimens – examples: FUFA FOLFOX ABVD BEACOPP fluorouracil, folinic acid folinic acid, fluorouracil, oxaliplatin doxorubicin, bleomycin, vinblastine, dacarbazine bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristin, procarbazine, prednisone Combination of cytostatics „Targeted therapy“in oncology Targeted therapy in oncology (biological therapy) „target“ should be on A/ tumor cells -Cell membrane receptor – extracellular part or/ intracellular signalling pathway B/ immune system (specific T-cells) – cancer immunotherapy -Immune check-point inhibitors (anti-CTLA-4 or anti-PD(L)1)