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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