Anticancer drugs. Methotrexate. 34.01. Diagram of the main targets for anticancer
drug therapy. Pyrimidine synthesis. Ribonucleotides. Deoxyribonucleotides.
34.01
Methotrexate
Anticancer drugs
Diagram of the main targets for anticancer drug therapy Pyrimidine synthesis
Purine synthesis
Ribonucleotides
Deoxyribonucleotides
DNA
RNA (transfer, messenger, ribosomal) Proteins Enzymes
Receptors Microtubules
Antimetabolite anticancer drug Actions Interferes with purine synthesis and the synthesis of thymidylate and thus with DNA synthesis.
Methotrexate
MOA Competitively inhibits dihydrofolate reductase (DHFR).
Abs/Distrb/Elim Given orally, i.v., i.m., or intrathecally; taken up into cells by the folate transport system. Clinical use Acute lymphoblastic leukemia in children; choriocarcinoma; tumours of head, neck breast & lung. Adverse effects Myelosupression, GIT disturbances, mucositis and sometimes pneumonitis.
Methotrexate
DHFR
DHFR FH4
Folic acid
FH2
dTMP
FH4 + 1-carbon unit
Thymidylate synthetase
dUMP
FH2 = dihydrofolate FH4 = tetrahydrofolate dTMP = thymidylate dUMP = uridylate
Special points High-dose regimens should be followed by ‘rescue’ with folinic acid – a form of tetrahydrofolate – to minimise toxic effects on the bone marrow and GIT mucosa. R&D 6e Ch 51, pp. 726-727; :D&H 2e p.105
34.02
Fluorouracil
Anticancer drugs
Diagram of the main targets for anticancer drug therapy Pyrimidine synthesis
Purine synthesis
Ribonucleotides Methotrexate inhibits purine synthesis and dTMP synthesis
Deoxyribonucleotides
DNA
RNA (transfer, messenger, ribosomal) Proteins Enzymes
Receptors Microtubules
Fluorouracil
Antimetabolite anticancer drug
Actions Interferes with the synthesis of dTMP and thus with DNA synthesis.
Methotrexate
MOA Gives rise to a fraudulent nucleotide and Inhibits thymidylate synthetase.
Abs/Distrb/Elim Given i.v.
Clinical use Cancers of GIT (gastric, colorectal ), pancreas, breast; malignant skin conditions.
DHFR
DHFR FH4
Folic acid
FH2
dTMP
FH4 + 1-carbon unit
Thymidylate synthetase
dUMP
FH2 = dihydrofolate
Adverse effects Not common: myelosuppression, GIT disturbances, mucositis. Given long term: desquamation of feet & hands.
FH4 = tetrahydrofolate dTMP = thymidylate dUMP = uridylate
Fluorouracil
Special points High-dose regimens should be followed by ‘rescue’ with folinic acid – a form of tetrahydrofolate – to minimise toxic effects on the bone marrow and GIT mucosa. R&D 6e Ch 51, pp. 726-727; :D&H 2e p.105
34.03
Mercaptopurine
Anticancer drugs
Diagram of the main targets for anticancer drug therapy Pyrimidine synthesis
Purine synthesis
Ribonucleotides Methotrexate inhibits purine synthesis and dTMP synthesis
Fluorouracil inhibits dTMP synthesis
Deoxyribonucleotides
DNA
RNA (transfer, messenger, ribosomal) Proteins Enzymes
Receptors Microtubules
Antimetabolite anticancer drug
Mercaptopurine
Actions & MOA Purine analogue that inhibits purine synthesis and gives rise to a fraudulent nucleotide.
Abs/Distrb/Elim Given orally.
Clinical use Acute leukemias and chronic myeloid leukemia.
Adverse effects Myelosuppression, hepatotoxicity, immunosuppression. Rare: pancreatitis, GIT ulceration.
Special points Note that azathioprine, an immunosuppressant agent, is metabolised to mercaptopurine.
Similar drug Pentostatin, also a purine analogue, inhibits adenosine deaminase – important in generation of inosine, an early stage of ribonucleic acid synthesis. R&D 6e Ch 51, pp. 726-727; :D&H 2e p.104
34.04
Cytarabine
Anticancer drugs
Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis
Pyrimidine synthesis
Purine synthesis
Ribonucleotides Fluorouracil inhibits dTMP synthesis
Deoxyribonucleotides
DNA
RNA (transfer, messenger, ribosomal) Proteins Enzymes
Receptors Microtubules
Antimetabolite anticancer drug
Cytarabine
Actions & MOA Pyrimidine analogue that is converted in the cell to the trisphosphate which inhibits DNA polymerase.
Abs/Distrb/Elim Given i.v., subcut. or intrathecally.
Clinical use Acute myeloblastic leukemia.
Adverse effects Marked myelosuppression. GIT disturbances; cerebellar ataxia.
Special points Careful haematological monitoring necessary.
R&D 6e Ch 51, p. 726; :D&H 2e pp.104-105
34.05
Bleomycin
Anticancer drugs
Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis
Pyrimidine synthesis
Purine synthesis
Ribonucleotides Fluorouracil inhibits dTMP synthesis
Deoxyribonucleotides
Cytarabine inhibits DNA synthesis
DNA
RNA (transfer, messenger, ribosomal) Proteins Enzymes
Receptors Microtubules
Cytotoxic antibiotic anticancer drug
Bleomycin
Actions & MOA Causes DNA fragmentation.
Abs/Distrb/Elim Given i.v. or i.m.
Clinical use Squamous cell cancer, metastatic germ cell cancer. Non-Hodgkin’s lymphoma.
Adverse effects Dose-related pulmonary fibrosis; skin toxicity (pigmentation, subcutaneous sclerotic plaques); mucositis; transient hypersensitivity reactions. Minimal myelosuppression.
R&D 6e Ch 51, p. 728; :D&H 2e pp.104-105
34.06
Cisplatin
Anticancer drugs
Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis
Pyrimidine synthesis
Purine synthesis
Ribonucleotides Fluorouracil inhibits dTMP synthesis
Deoxyribonucleotides
Cytarabine inhibits DNA synthesis
Bleomycin damages DNA
DNA
RNA (transfer, messenger, ribosomal) Proteins Enzymes
Receptors Microtubules
Cytotoxic anticancer drug
Cisplatin
Actions & MOA Forms a reactive complex that causes intrastrand cross-linking and denaturation of the DNA.
Abs/Distrb/Elim Given by i.v. infusion. Can be given to outpatients.
Clinical use Cancers of testes, ovaries, cervix, bladder, lung and head & neck.
Adverse effects Nephrotoxicity, ototoxicity, severe nausea & vomiting, myelosuppression, peripheral neuropathy, hypomagnesaemia.
Drug with Carboplatin: more myelosuppressive but other adverse effects less marked so better tolerated; similar action preferred for ovarian cancer.
R&D 6e Ch 51, p. 725; :D&H 2e pp.104-105
34.07
Cyclophosphamide
Anticancer drugs
Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis
Pyrimidine synthesis
Purine synthesis
Ribonucleotides Fluorouracil inhibits dTMP synthesis
Deoxyribonucleotides
Bleomycin damages DNA
Cytarabine inhibits DNA synthesis
Cisplatin crosslinks DNA strands
DNA
RNA (transfer, messenger, ribosomal) Proteins Enzymes
Receptors Microtubules
Alkylating anticancer drug
Cyclophosphamide
Actions & MOA Cross-links DNA by forming covalent bonds with guanine residues on each strand, interfering with cell division and triggering apoptosis.
Abs/Distrb/Elim Given orally or i.v. Metabolised in the liver to phosphoramide mustard (the active moiety) and acrolein.
Clinical use Chronic lymphocytic leukemia, soft tissue sarcoma, osteogenic sarcoma, ovarian & breast cancers.
Adverse effects Nausea & vomiting; myelosuppression; acrolein-mediated haemorrhagic cystitis; alopecia. Gametogenesis can be affected. Prolonged use can result in acute non-lymphocytic leukemia.
R&D 6e Ch 51, p. 724; :D&H 2e pp.104-105
34.08
Doxorubicin
Anticancer drugs
Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis
Pyrimidine synthesis
Purine synthesis
Ribonucleotides
Fluorouracil inhibits dTMP synthesis
Deoxyribonucleotides Bleomycin damages DNA
Cytarabine inhibits DNA synthesis
Cisplatin crosslinks DNA strands
DNA
Cyclophosphamide intercalates & cross-links
RNA (transfer, messenger, ribosomal) Proteins Enzymes
Receptors Microtubules
Cytotoxic anticancer drug
Doxorubicin
Actions & MOA Inhibits DNA and RNA synthesis through an effect on topoisomerase II.
Abs/Distrb/Elim Given by infusion (extravasation can cause tissue damage); by bladder instillation for bladder cancers.
Clinical use Acute leukemias; Hodgkin & non-Hodgkin lymphomas; tumours of breast, ovary, bladder, bronchi.
Adverse effects Dose-related cardiac damage; nausea & vomiting; myelosuppression; hair loss.
R&D 6e Ch 51, p. 727-728; :D&H 2e pp.104-105
34.09
Irinotecan
Anticancer drugs
Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis
Pyrimidine synthesis
Purine synthesis
Fluorouracil inhibits dTMP synthesis
Ribonucleotides Bleomycin damages DNA
Deoxyribonucleotides
Cisplatin crosslinks DNA strands Cyclophosphamide intercalates & cross-links
Cytarabine inhibits DNA synthesis
DNA
Doxorubicin intercalates & inhibits topoisomerase II
RNA (transfer, messenger, ribosomal) Proteins Enzymes
Receptors Microtubules
Cytotoxic anticancer drug (plant derived)
Irinotecan
Actions & MOA Binds to and inhibits topoisomerase I, thus interfering with cell proliferation.
Abs/Distrb/Elim Given by i.v. infusion
Clinical use Metastatic tumours of colon and rectum (in combination with other agents).
Adverse effects
GIT disturbances, interstitial pulmonary disease.
R&D 6e Ch 51, p. 729; D&H 2e pp.104-105
34.10
Dactinomycin
Anticancer drugs
Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis
Pyrimidine synthesis
Purine synthesis
Fluorouracil inhibits dTMP synthesis
Ribonucleotides
Bleomycin damages DNA Cisplatin crosslinks DNA strands
Deoxyribonucleotides
Cyclophosphamide intercalates & cross-links
Cytarabine inhibits DNA synthesis
Doxorubicin intercalates & inhibits topoisomerase II
DNA
Irinotecan inhibits topoisomerase I
RNA (transfer, messenger, ribosomal) Proteins Enzymes
Receptors Microtubules
Anticancer antibiotic
Dactinomycin
Actions & MOA Intercalates in the DNA and inhibits RNA polymerase and topoisomerase II.
Abs/Distrb/Elim Given by i.v. injection.
Clinical use Paediatric cancers.
Adverse effects
Nausea & vomiting; myelosuppression; hair loss.
R&D 6e Ch 51, p. 728; D&H 2e pp.104-105
34.11
Vincristine
Anticancer drugs
Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis
Pyrimidine synthesis
Purine synthesis
Fluorouracil inhibits dTMP synthesis
Ribonucleotides
Bleomycin damages DNA Cisplatin crosslinks DNA strands
Deoxyribonucleotides
Cyclophosphamide intercalates & cross-links
Cytarabine inhibits DNA synthesis
Doxorubicin intercalates & inhibits topoisomerase II
DNA
Dactinomycin inhibits topoisomerase II and RNA polymerase
Irinotecan inhibits topoisomerase I
RNA (transfer, messenger, ribosomal) Proteins Enzymes
Receptors Microtubules
Anticancer vinca alkaloid
Vincristine
Actions & MOA Binds to tubulin, preventing spindle formation in dividing cells stopping them in mitosis.
Abs/Distrb/Elim Given by i.v. injection.
Clinical use Leukemias, lymphomas, breast and lung cancers.
Adverse effects
Nausea & vomiting; hair loss; neurotoxicity (peripheral & autonomic); negligible myelosuppression.
R&D 6e Ch 51, p. 728-729; D&H 2e pp.104-105
34.12
Paclitaxel
Anticancer drugs
Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis
Pyrimidine synthesis
Purine synthesis
Fluorouracil inhibits dTMP synthesis
Ribonucleotides
Bleomycin damages DNA Cisplatin crosslinks DNA strands
Deoxyribonucleotides
Cyclophosphamide intercalates & cross-links
Cytarabine inhibits DNA synthesis
Doxorubicin intercalates & inhibits topoisomerase II
DNA
Dactinomycin inhibits topoisomerase II and RNA polymerase
Irinotecan inhibits topoisomerase I
RNA (transfer, messenger, ribosomal) Proteins Enzymes
Receptors Microtubules
Vincristine inhibits microtubule function
Anticancer yew tree derivative
Paclitaxel
Actions & MOA Binds to tubulin, keeping microtubules polymerised (‘frozen’), preventing spindle formation in dividing cells and stopping them in mitosis.
Abs/Distrb/Elim Given by i.v. infusion.
Clinical use Cancers of ovary and breast, non-small-cell lung cancer.
Adverse effects Hypersensitivity reactions, myelosuppression, peripheral neuropathy, bradycardia, muscle & joint pain, hair loss. GIT disturbance: moderate.
R&D 6e Ch 51, p. 728-729; D&H 2e pp.104-105
34.13
Imatinib
Anticancer drugs
Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis
Pyrimidine synthesis
Purine synthesis
Fluorouracil inhibits dTMP synthesis
Ribonucleotides
Bleomycin damages DNA Cisplatin crosslinks DNA strands
Deoxyribonucleotides
Cyclophosphamide intercalates & cross-links
Cytarabine inhibits DNA synthesis
Doxorubicin intercalates & inhibits topoisomerase II
DNA
Dactinomycin inhibits topoisomerase II and RNA polymerase
Irinotecan inhibits topoisomerase I
RNA (transfer, messenger, ribosomal) Proteins Enzymes
Receptors Microtubules
Vincristine, paclitaxel inhibit microtubule function
Anticancer protein kinase inhibitor
Imatinib
Actions & MOA Inhibits protein kinases important in chronic myeloid leukemia and other malignancies.
Abs/Distrb/Elim Given orally, well absorbed.
Clinical use Chronic myeloid leukemia, acute lymphoblastic leukemia, GIT stromal tumours, chronic eosinophilic leukemia, myeloproliferative diseases.
Adverse effects GIT disturbances, abdominal pain, oedema, haemorrhage, cough, dyspnoea, paraesthesia, arthralgia, conjunctivitis, photosensitivity, headache, dizziness, sweating, rash.
R&D 6e Ch 51, p. 730-731; D&H 2e pp.104-105
34.14
Trastuzumab
Anticancer drugs
Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis
Pyrimidine synthesis
Purine synthesis
Fluorouracil inhibits dTMP synthesis
Ribonucleotides
Bleomycin damages DNA Cisplatin crosslinks DNA strands
Deoxyribonucleotides
Cyclophosphamide intercalates & cross-links
Cytarabine inhibits DNA synthesis
Doxorubicin intercalates & inhibits topoisomerase II
DNA
Dactinomycin inhibits topoisomerase II and RNA polymerase
Irinotecan inhibits topoisomerase I
RNA (transfer, messenger, ribosomal) Proteins Imatinib protein kinase inhibitor
Enzymes
Receptors Microtubules
Vincristine, paclitaxel inhibit microtubule function
Monoclonal antibody anticancer agent
Trastuzumab
Actions & MOA Binds to and inhibits the epidermal growth factor receptor (a tyrosine kinase receptor), preventing its activation and inhibiting cell proliferation.
Abs/Distrb/Elim Given by i.v. infusion.
Clinical use Breast cancers.
Adverse effects GIT disturbances, abdominal pain, hypersensitivity reactions, cardiac toxicity, paraesthesia, headache, dizziness, anxiety, depression, oedema, arthralgia, bruising, bone pain, leg cramps, rash, alopecia.
R&D 6e Ch 51, p. 730-731; D&H 2e pp.104-105
34.15
Tamoxifen
Anticancer drugs
Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis
Pyrimidine synthesis
Purine synthesis
Fluorouracil inhibits dTMP synthesis
Ribonucleotides
Bleomycin damages DNA Cisplatin crosslinks DNA strands
Deoxyribonucleotides
Cyclophosphamide intercalates & cross-links
Cytarabine inhibits DNA synthesis
Doxorubicin intercalates & inhibits topoisomerase II
DNA
Dactinomycin inhibits topoisomerase II and RNA polymerase
Irinotecan inhibits topoisomerase I
RNA (transfer, messenger, ribosomal) Proteins Imatinib protein kinase inhibitor
Enzymes
Receptors Microtubules
Trastuzumab antibody v EGRF 2 (epidermal growth factor receptor 2) Vincristine, paclitaxel inhibit microtubule function
Oestrogen receptor agonist
Tamoxifen
Actions & MOA Competes with endogenous oestrogen for the oestrogen receptor, preventing cell activation and proliferation.
Abs/Distrb/Elim Given orally.
Clinical use Breast cancer.
Adverse effects Hot flushes, GIT disturbances, headache, menstrual irregularities.
R&D 6e Ch 51, p. 729-730; D&H 2e pp.104-105
34.16
Crisantaspase
Anticancer drugs
Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis
Pyrimidine synthesis
Purine synthesis
Fluorouracil inhibits dTMP synthesis
Ribonucleotides
Bleomycin damages DNA Cisplatin crosslinks DNA strands
Deoxyribonucleotides
Cyclophosphamide intercalates & cross-links
Cytarabine inhibits DNA synthesis
Doxorubicin intercalates & inhibits topoisomerase II
DNA
Dactinomycin inhibits topoisomerase II and RNA polymerase
Irinotecan inhibits topoisomerase I
RNA (transfer, messenger, ribosomal) Proteins Imatinib protein kinase inhibitor
Enzymes
Receptors Microtubules
Trastuzumab antibody v EGRF 2 (epidermal growth factor receptor 2) Tamoxifen, an antioestrogen Vincristine, paclitaxel inhibit microtubule function
A preparation of the enzyme asparaginase used as an anticancer agent
Crisantaspase
Actions & MOA Breaks down asparagine and is active in tumours (e.g. acute lymphoblastic leukemia) that have lost the ability to synthesise asparagine and require an external source.
Abs/Distrb/Elim Given i.v., i.m. or subcut.
Clinical use Acute lymphoblastic leukemia.
Adverse effects Nausea & vomiting, CNS depression, liver disorder, anaphylactic reactions, risk of hyperglycaemia.
R&D 6e Ch 51, p. 730; D&H 2e pp.104-105
34.17
Anticancer drugs
What are the main adverse effects of anticancer drugs?
Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis
Pyrimidine synthesis
Purine synthesis
Fluorouracil inhibits dTMP synthesis
Ribonucleotides
Bleomycin damages DNA Cisplatin crosslinks DNA strands
Deoxyribonucleotides
Cyclophosphamide intercalates & cross-links
Cytarabine inhibits DNA synthesis
Crisantaspase deaminates asparagine, inhibits protein synthesis Imatinib protein kinase inhibitor
Doxorubicin intercalates & inhibits topoisomerase II
DNA
Dactinomycin inhibits topoisomerase II and RNA polymerase
Irinotecan inhibits topoisomerase I
RNA (transfer, messenger, ribosomal) Proteins Enzymes
Receptors Microtubules
Trastuzumab antibody v EGRF 2 (epidermal growth factor receptor 2) Tamoxifen, an antioestrogen Vincristine, paclitaxel inhibit microtubule function
The main adverse effects of anticancer drugs Most anticancer drugs are cytotoxic (they damage or kill cells) and they are antiproliferative (they stop cells from dividing – both cancer cells and rapidly dividing normal cells). Thus they can: • depress the bone marrow • impair healing • interfere with normal growth (in children) • cause sterility • result in hair loss • be teratogenic Most also cause nausea and vomiting. Different cytotoxic drugs manifest the above adverse effects to different degrees. Examples are the drugs that affect DNA & RNA synthesis and actions (see figure on the face of this card)
Newer, non-proliferative agents target the underlying pathogenic mechanisms such as changes in: • the relevant growth factors and/or their receptors • cell cycle control mechanisms • apoptotic pathways • telomerase expression • tumour-related angiogenesis These agents are less likely to have the above cytotoxic actions but have their own adverse effects. Examples are the drugs that don’t affect DNA & RNA synthesis (see the face of this card) R&D 6e Ch 51, pp. 718-722; D&H 2e pp.104-105
