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Flashcards in Anticancer Deck (111):
1

Adenocarcinomas

epithelial lining ducts. Lung, colon, breast, pancreas, stomach, oesophagus, prostate, ovary, endometrium

2

Squamous cell cancers

Protective barrier epithelium. Skin, nasal cavity, larynx, lung, cervix, oesophagus

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Metastasis Rx

Chemotherapy

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Invasive tumour treatment

resection with wide margin of non-malignant tissue.

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Characteristics of normal cells versus malignant, transformed cells

NORMAL: growth in serum-containing medium. Contact inhibition. low density of growth. Require substratum/anchorage. ECM. Organised actin microfilaments. Flat. senescence on crisis. non tumorigenic. TRANSFORMED: grow in low/absent serum medium. no contact inhibition. high density growth. anchorage independent. little ECM. Disorganised microfilaments. rounded. immortal. indice tumours.

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Properties of cancer

ESCAPE MECHANISMS OF REGULATION OF NORMAL GROWTH AND DIVISION. Evading apoptosis, sustained angiogenesis, no maximum replication, tissue invasion & metastasis, insensitive to anti-growth signals. self-sufficiency in growth signals.

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Main target of cell cycle for cancer drugs

S phase when DNA is replicated. As G1 phase is when cells rest, it is variable in length and often is short in cancer cells most cells will be in S phase.

8

Epigenetic factors of cancer and what epigenetic is

Epigenetic = modifications in gene expression but no change in genome cause changes in phenotype of organism. E.g: Methylation of specific Cytosine in promoters or changes in chromatin structure independent of DNA.

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Overactivity mutation cancers and example

Oncogene. activating cell proliferation. Need one copy of gene mutation. e.g: Philadelphia chromosome in chromic myeloid leukaemia.

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Underactivity/loss of function mutations in cancer and example

Tumour suppressor gene. Need 2 copies of gene. Inactivate function tumour suppressor gene so no cell proliferation. E.g: p53 protein from the TP53 gene is mutated in over half of all cancers.

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function of proto-oncogenes

growth factor, growth factor receptors, singal transduction, nuclear proto-oncogenes and transcription factors.

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Mutation in DNA replication error repair

linked to colon cancer. small adenoma to large adenoma to carcinoma progression.

13

Types of anti-cancer drugs targeting DNA synthesis and replication and cell division

Antimetabolites e.g. methotrexate, 5-fluorouracil. Antibiotics e.g. Dactomysin. Alkylating agents e.g. temezolomide. Platinum-Coordination Complexes e.g. Cisplatin. Topoisomerase 1 and 2 inhibitors. Tolomerase inhibitors. Mitosis targeting agents e.g. vincristine.

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Cell-cycle specific drugs

Antimetabolistes, Bleomycin peptide antibiotics, Vinca alkylating agents and Etoposide. Effective for high growth fraction malignancies.

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Cell-cycle non specific drugs

Alkylating agents. Antibiotics, cisplatin, Nitrosoureas. Effective for high and low growth fraction malignancies.

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Examples of antimetabolites and common characteristics

Analogous to cell compound interfere with DNA/RNA synethsis in S phase. Methotrexate, 6-mercaptopurine, 5-fluorouracil, Gemcitabine, cytarabine.

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Methotrexate mode of action

Analogous to folic acid- competitively inhibits dihydrofolate reductase by binding to the enzyme with a higher affinity than the endogenous ligand dihydrofolate.

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Pharmacodynamics of Methotrexate

Poor BBB crossing as low lipid solubility. Low cell efflux as converted to MTX-polyglutamate. Reduce toxicity with co-adminsitration of Leucovorin an analogue for tetrahydrofolate. Targets S phase.

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Use of methotrexate

ALL, breast, head, neck and rheumatoid arthritis and other autoimmune diseases.

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Pharmacokinetics of methotrexate

IM/IV or intrathecal as poor CNS penetration. Need good patient hydration. Kidney/urine excretion.

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6-Mercaptopurine action

Purine antimetabolite drug which has analogous structure to purine. Phosphorylated in cell to active form. Prevents the formation of proper nucleotides for DNA/RNA. Triphosphate form can be incorporated into RNA strand can create non-functional strand.

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Use of 6-mercaptopurine

in maintaining remission of ALL

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Pharmacokinetics of 5-mercaptopurine and resistance

Not CNS penetrating. Urine excretion. Resistance due to mutations in gene which creates active form from pro-drug or increasing metabolism.

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5-Fluorouracil action

Pro-drug requiring phosphorylation to create 'fraudulent nucleotide' with analogous structure to pyrimidine. Reduces DNA precursor molecules by competing for enzyme for dTMP production from DUMP = thymidylate synthetase. S phase acting drug.

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Administration,. excretion and other info on 5-Fluorouracil

commonly with MTX. can penetrate to CNS. IV administration. urine excretion.

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Gemcitabine action

Analogy to deoxycytidine triphosphate nucleotide, incorporated into DNA chain in S phase creating null product.

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Use of gemcitabine

IV. Advanced metastatic pancreatic cancer. not curative

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Pharmacology of gemcitabine

Urine excretion. IV infusion. Myelosuppression major ADR. Non-toxic product when deaminated.

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Cytarabine action

S phase of DNA synthesis. Pyrimidine analogue that is phosphorylated to cytosine arabinoside and is incorporated into strand. Inhibits DNA polymerase.

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Pharmacology of Cytarabine

IV or intrathecal. Urine excretion. toxic ADR including myelosuppression.

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Examples of antibiotic anti cancer chemotherapy and common action

Dactinomysin and Anthracyclines such as Doxorubicin, Bleomycin and Daunorubicin. bind to DNA and disrupt function.

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Dactinomysin action

Intercalates into minor groove of DNA between adjacent G and C nucleotide pairs. Prevents RNA polymerase movement along chain so no synthesis.

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use of dactinomysin

with MTX. Mostly in paediatric cancers. Resistance can occur with P-glycoprotein.

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Pharmacokinetics of dactinomysin

Poor CNS penetration. IV. bile and urine excretion.

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Anthracyclines action

Intercalate into DNA. Oxidase lipids and generate free radicals (superoxides) which damage DNA. Also act to prevent action of DNA breakage repair system by inhibiting topoisomerase 2 which breaks DNA but with drug present can not rejoin the strand. target S and G2 phase.

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Use of anthracyclines

In combo therapy for breast, lung and leukaemia.

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Pharmacokinetics of anthracyclines

Bile and urine excretion. poor CNS penetration.

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Examples of alkylating agents

Mechlorethamine, cyclophosphamide, ifosphamide, carmustine, dacarbazine, temezolomide

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Action of alkylating agents

Transfer alkyl to DNA giving rise to mutations and cause cross-linking within DNA helix. Most impact in S phase.

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Pharmacokinetics of alkylating agents

Some need CYP metabolism to active form. Oral or IV. Temozolomide can penetrate to CNS. urine excretion.

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Use of alkylating agents

combo treatment for solid e.g. brain and lymphatic tumours

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Examples of platinum coordinatiion complexes

cisplatin, carboplatin, oxaliplatin

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Action of platinum coordination complexes

Chloride dissociation from complex creates toxic and reactive species. Incooperate platinum into DNA forms intra and inter-genome strand cross links so unable to carry out replication and transcription. G1 and S phase.

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Use of platinum coordination complexes

Solid tumours: testicular (in combo) or bladder (mono) and ovarian. Oxaliplatin used in colorectal cancer.

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Pharmacology of platinum coordination complexes

IV. poor CNS penetration. Urine excretion.

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Examples of topoisomerase 1 inhibitors

Topotecan, irinotecan

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Action of topoisomerase 1 inhibitors

S phase. Topoisomerase 1= Relax supercoil and separate genome strands, relieve tension. Inhibitors bind to enzyme attached to DNA prevent re-ligation and sealing = broken genome.

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Use of topoisomerase 1 inhibitors

Topotecan = metastatic ovarian cancer and lung cancer. Irinotecan = colon and rectal cancer in combo with 5-FU and leucovorin.

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Pharmacology of topoisomerase 1 inhibitors

Irinotecan needs metabolism to active drug in cancer cell. Urine excretion. IV. Myelosuppression with topotecan.

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Topoisomerase 2 inhibitor examples

Daunorubicin and Doxorubicin. Etoposide and Teniposide

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Action of topoisomerase 2 inhibitors

Topoisomerase 2 helps DNA relax by forming non-cleavable intermediate complexes. Etoposide and Teniposide bind to transient enzyme and DNA complex = double strand breakage. D and D cataylse the break but not repair of DNA strands. S PHASE

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Use of topoisomerase 2 inhibitors

Etoposide = in combo with bleomycin and cisplatin for testicular cancer. Teniposide = ALL, glioma and neuroblastoma.

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Pharmacology of topoisomerase 2 inhibitors and origin

urine excreted. IV and etoposide is oral. Natural compound derivatives.

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Action of tolomerase

reverse transcription. copies telomeres to prevent shortening of them in replication. Active in malignant but not normal cells. Gives immortality to cancer cells and senescence to normal ones.

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Example of telomerase inhibitors

Imetelstat (in trial). prevent immortality of cancer cells.

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Mitosis targetted anti-cancer chemotherapy examples and common action

Vinca alkaloids and Tazanes. Target M phase.

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Vinca alkaloids Action

Block metaphase. Bind to tubulin and prevent polymerisation into microtubles for organisation of chromosomes. Use in rapidly dividing tumours. Resistance can occur. Also inhibit other functions of microtubules such as axonal transport in neurones and chemotaxis.

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Taxanes examples

e.g. Paclitaxel and docetaxel

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Vinca alkaloid examples

Vincristine and vinblastine

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Taxane action

block metaphase of mitosis. bind to tubulin and promote polymerization but prevent chromosome segregation action.

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Angiogenesis

Formation of new blood vessels to increase Po2 of tumour. target for anti-cancer drugs

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Current treatments for cancer and difficulties in chemotherapy for cancer

Surgical, irradiation and chemotherapy. As cancer and human cells are not as dissimilar as microorganisms more difficult to target infected cells.

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3 genetic components of cancer

Proto-oncogenes mutating to oncogenes. Mutations in tumour suppressor genes. Mutations in DNA repair.

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Resistance to methotrexate

Not effective for stimulating apoptosis in Melanoma tumours, been shown to be due to poor uptake into the cells possibly via the alpha-folate receptor (2009). resistance is also emerging for use in acute lymphoblastic leukaemia.

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Use of 5-Fluorouracil

Breast, colorectal, anal, stomach, pancreas, oesophagus, liver, head, neck and bladder carcinomas. Topical administration can be used for skin cancers

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Use of cytarabine

Acute non-lymphocytic leukaemia

67

Bleomycins

Derivative of anthracyclines. Metal-chelating glyco-peptide antibiotics. Cause chain fragmentation and release free bases. Generate free radicals and destructive oxygen species. Most effective in G2 phase. Little myleopsuppression but can cause pulmonary fibrosis.

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ADR of alkylating agents

Kill other rapidly dividing cells: decrease gametogenesis, teratogenic, bone marrow suppression, immunosuppressant, nausea and vomiting. Carcinogenic to normal cells = increase risk of non-lymphocytic leukaemia.

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ADR of platinum compounds

Nephrotoxic. nausea and vomiting (use with serotonin 3 antagonist e.g. ondansetron).

70

Origin of topoisomerase 1 inhibitors

Natural - derive from camptothecin, a compound in a tree.

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Vinca Alkaloids ADR and origin

ADR of peripheral neuropathy, reversible hair loss and myelosuppression. Natural compounds.

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Use of taxanes

RX for breast cancer. Use in combo with a platinum compound for advanced ovarian cancer. Also use in non-small cell lung cancers

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ADR and origin of taxanes

ADR: neutropenia, bone marrow suppression, neurotoxicity, fluid retention. Resistance possible. Semi-synthetic but derivative of yew tree bark compound

74

Natural anticancer chemotherapies

Vinca alkaloids, taxanes, camptothecins, antibiotics and anthracyclines.

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Example of selective oestrogen receptor modulator and use

Tamoxifen. In hormone-dependent breast cancer.

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Tamoxifen action

Anti-oestrogen chemotherapy. Competes for intracellular, oestrogen receptor with endogenous oestrogen, binding inhibits the conformational change which initiates transcription of oestrogen-responsive genes, protein produce cause cell growth and proliferation. Therefore the alternative ligand prevents this.

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Unwanted effects of selective oestrogen receptor modulator

Act as weak oestrogen steroids so could induce opposite effect and stimulate the tumour growth - use limited to 5 years. Hyperplastic changes to endometrium. Thromboembolism.

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Use of selective oestrogen receptor modulator in post-menopausal women

Use with a gonadotropin releasing hormone analogue e.g. leuprolide to lower oestrogen production.

79

Excretion of Tamoxifen

in faeces.

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Alternative, non-steroidal option for breast cancer (esp in post-menopausal women)

Aromatase inhibitors

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Action of aromatase inhibitors

Prevent peripheral synthesis of oestrogen in tissues such as fat and liver. To produce the oestrogen from androgen need the enzyme aromatase.

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Example of aromatase inhibitors

Anastrozole and Letrozole

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Treatment of prostate cancer

Antiandrogens. Androgen receptor antagonists. Flutamide, Bicalutamide and Cyproterone Non-steroidal. Bioavailable orally and excreted in the urine.

84

2 examples of Oncogene cancers and potential treatments

Epidermal Growth Factor Receptor (Erb-B)=> cytoplasmic tyrosine kinase inhibitor e.g. Iressa and Tarceva treat occurrence in lung and breast (HER2) cancers.
BCR-ABL Fusion Protein=> in chronic myeloid leukaemia. Treat with tyrosine kinase inhibitor e.g Imatinib.

85

Example of tumour suppressor gene cancer and potential treatment

P53 protein is mutated in over 50% of human cancers. It forms a complex with the oncogene MDM2 which degrades the p53 protein. Nutlins bind to MDM2 and release the p53 protein so activate apoptosis of the cell NOT CLINICALLY USED.

86

Oncogene in melanomas and targeted treatment

B-raf - a serine/threonine protein kinase. Inhibitors of b-raf used in melanoma treatment.

87

use of Raf inhibitors

Nexavar - renal cancer also has action on tyrosine kinase. b-raf inhibitors in melanoma.

88

Action of monoclonal antibodies

Prevent binding of growth factors to cell. Initiate an immune response on cell. Conjugated to a toxin or radioisotope.

89

Production of monoclonal antibody

Produced by hybridoma cell cultures which react to a pre-defined, specific target on cancer cells. They are commonly murine or primate and must be humanised to prevent rejection or an immune response on them when administered to patients.

90

New developments in monoclonal antibody production

Create single chain variable region fragments made up of fragments of the antibody not the whole structure. Improve the penetration of the drug.

91

Examples of monoclonal antibodies used

Herceptin/Trastuzumab, Rituximab, Bevacizumab and Cetuximab.

92

Herceptin/Trastuzumab use and action

Target extracellular domain of HER2 in breast cancer reduce proliferation of cells over-expressing this receptor. HER2 has tyrosine kinase activity. Used in progesterone-receptor-tamoxifen-resistant cancers or none-alpha-oestrogen-receptor-expressing cancers

93

Herceptin/Trastuzumab administration, ADR

IV, can be given with other chemotherapy e.g. paclitaxel. ADR = heart failure.

94

Bevacizumab use and action

used in colorectal cancers. restrains the action of vascular endothelial growth factor A. Decrease angiogenesis.

95

Administration of Bevacizumab and ADR

Often with 5-Fluorouracil. IV. ADR = hypertension and interstitial bleeding.

96

Rituximab use and action

Used in Non-hodgkin lymphoma and leukaemia. Fab region of drug binds to CD20 (calcium channel forming) on B lymphocytes and lyses cell. Activates complement factor in immune system.

97

Administration and ADR of Rituximab

IV. can be given in combo with other chemotherapeutics e.g. cyclophosphamide. ADR: hypotension, fever, cardiac pathologies

98

Cetuximab use and action

Targets epithelial growth factor. Used in colorectal cancer treatment

99

Administration and ADRs of Cetuximab

IV in combo with irinotecan. ADR = fever, hypotension.

100

recombinant enzyme example

L-Asparaginase

101

Use of L-asparaginase

Childhood acute lymphocytic anaemia with prednisolone and vincristine. Used in tumours with low asparagine concs

102

Mode of action of l-asparaginase

Neoplastic cells have low asparagine synthetase levels so require host to make sufficient asparagine. The drug depletes the blood levels of asparagine so tumour can not get enough.

103

Two types of interferons

type 1 IFNs with alpha and beta and type 2 IFN with gamma.

104

Action of interferons

Promote apoptosis in cancer cells, stimulate immune recognition of cancer cells.

105

Use of interferons in cancer treatment

IFN-α2a and IFN-α2b - Interferon ALPHA. Used in Melanoma, renal cell carcinoma, Kaposi sarcoma HIV associated.

106

Administration of interferon alpha

IM, sub cut or IV.

107

Interleukins in cancer treatment

Interleukin 2 used in renal cell carcinoma and melanoma. Potentially interleukin-12 too

108

Action of interleukin 2

T lymphocyte growth factor. May act synergistically with IFNα2a.

109

ADR of interleukin 2 use

Hypotension, liver damage. REVERSIBLE. MAX dose of 14 due to tolerance.

110

Action of interleukin 12

Stimulates B and T cells and natural killer cells.

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What compound does interleukin 12 potentially interact with?

Granulocyte-monocyte colony stimulating factor. Which cam stimulate immune system response to cancer. Used after bone marrow or stem cell transplant.