Anticancer Flashcards
Adenocarcinomas
epithelial lining ducts. Lung, colon, breast, pancreas, stomach, oesophagus, prostate, ovary, endometrium
Squamous cell cancers
Protective barrier epithelium. Skin, nasal cavity, larynx, lung, cervix, oesophagus
Metastasis Rx
Chemotherapy
Invasive tumour treatment
resection with wide margin of non-malignant tissue.
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.
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.
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.
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.
Overactivity mutation cancers and example
Oncogene. activating cell proliferation. Need one copy of gene mutation. e.g: Philadelphia chromosome in chromic myeloid leukaemia.
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.
function of proto-oncogenes
growth factor, growth factor receptors, singal transduction, nuclear proto-oncogenes and transcription factors.
Mutation in DNA replication error repair
linked to colon cancer. small adenoma to large adenoma to carcinoma progression.
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.
Cell-cycle specific drugs
Antimetabolistes, Bleomycin peptide antibiotics, Vinca alkylating agents and Etoposide. Effective for high growth fraction malignancies.
Cell-cycle non specific drugs
Alkylating agents. Antibiotics, cisplatin, Nitrosoureas. Effective for high and low growth fraction malignancies.
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.
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.
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.
Use of methotrexate
ALL, breast, head, neck and rheumatoid arthritis and other autoimmune diseases.
Pharmacokinetics of methotrexate
IM/IV or intrathecal as poor CNS penetration. Need good patient hydration. Kidney/urine excretion.
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.
Use of 6-mercaptopurine
in maintaining remission of ALL
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.
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.
Administration,. excretion and other info on 5-Fluorouracil
commonly with MTX. can penetrate to CNS. IV administration. urine excretion.
Gemcitabine action
Analogy to deoxycytidine triphosphate nucleotide, incorporated into DNA chain in S phase creating null product.
Use of gemcitabine
IV. Advanced metastatic pancreatic cancer. not curative
Pharmacology of gemcitabine
Urine excretion. IV infusion. Myelosuppression major ADR. Non-toxic product when deaminated.
Cytarabine action
S phase of DNA synthesis. Pyrimidine analogue that is phosphorylated to cytosine arabinoside and is incorporated into strand. Inhibits DNA polymerase.
Pharmacology of Cytarabine
IV or intrathecal. Urine excretion. toxic ADR including myelosuppression.
Examples of antibiotic anti cancer chemotherapy and common action
Dactinomysin and Anthracyclines such as Doxorubicin, Bleomycin and Daunorubicin. bind to DNA and disrupt function.
Dactinomysin action
Intercalates into minor groove of DNA between adjacent G and C nucleotide pairs. Prevents RNA polymerase movement along chain so no synthesis.
use of dactinomysin
with MTX. Mostly in paediatric cancers. Resistance can occur with P-glycoprotein.
Pharmacokinetics of dactinomysin
Poor CNS penetration. IV. bile and urine excretion.
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.
Use of anthracyclines
In combo therapy for breast, lung and leukaemia.
Pharmacokinetics of anthracyclines
Bile and urine excretion. poor CNS penetration.
Examples of alkylating agents
Mechlorethamine, cyclophosphamide, ifosphamide, carmustine, dacarbazine, temezolomide
Action of alkylating agents
Transfer alkyl to DNA giving rise to mutations and cause cross-linking within DNA helix. Most impact in S phase.
Pharmacokinetics of alkylating agents
Some need CYP metabolism to active form. Oral or IV. Temozolomide can penetrate to CNS. urine excretion.
Use of alkylating agents
combo treatment for solid e.g. brain and lymphatic tumours
Examples of platinum coordinatiion complexes
cisplatin, carboplatin, oxaliplatin
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.
Use of platinum coordination complexes
Solid tumours: testicular (in combo) or bladder (mono) and ovarian. Oxaliplatin used in colorectal cancer.
Pharmacology of platinum coordination complexes
IV. poor CNS penetration. Urine excretion.
Examples of topoisomerase 1 inhibitors
Topotecan, irinotecan
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.
Use of topoisomerase 1 inhibitors
Topotecan = metastatic ovarian cancer and lung cancer. Irinotecan = colon and rectal cancer in combo with 5-FU and leucovorin.
Pharmacology of topoisomerase 1 inhibitors
Irinotecan needs metabolism to active drug in cancer cell. Urine excretion. IV. Myelosuppression with topotecan.
Topoisomerase 2 inhibitor examples
Daunorubicin and Doxorubicin. Etoposide and Teniposide
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
Use of topoisomerase 2 inhibitors
Etoposide = in combo with bleomycin and cisplatin for testicular cancer. Teniposide = ALL, glioma and neuroblastoma.
Pharmacology of topoisomerase 2 inhibitors and origin
urine excreted. IV and etoposide is oral. Natural compound derivatives.
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.
Example of telomerase inhibitors
Imetelstat (in trial). prevent immortality of cancer cells.
Mitosis targetted anti-cancer chemotherapy examples and common action
Vinca alkaloids and Tazanes. Target M phase.
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.
Taxanes examples
e.g. Paclitaxel and docetaxel
Vinca alkaloid examples
Vincristine and vinblastine
Taxane action
block metaphase of mitosis. bind to tubulin and promote polymerization but prevent chromosome segregation action.
Angiogenesis
Formation of new blood vessels to increase Po2 of tumour. target for anti-cancer drugs
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.
3 genetic components of cancer
Proto-oncogenes mutating to oncogenes. Mutations in tumour suppressor genes. Mutations in DNA repair.
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.
Use of 5-Fluorouracil
Breast, colorectal, anal, stomach, pancreas, oesophagus, liver, head, neck and bladder carcinomas. Topical administration can be used for skin cancers
Use of cytarabine
Acute non-lymphocytic leukaemia
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.
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.
ADR of platinum compounds
Nephrotoxic. nausea and vomiting (use with serotonin 3 antagonist e.g. ondansetron).
Origin of topoisomerase 1 inhibitors
Natural - derive from camptothecin, a compound in a tree.
Vinca Alkaloids ADR and origin
ADR of peripheral neuropathy, reversible hair loss and myelosuppression. Natural compounds.
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
ADR and origin of taxanes
ADR: neutropenia, bone marrow suppression, neurotoxicity, fluid retention. Resistance possible. Semi-synthetic but derivative of yew tree bark compound
Natural anticancer chemotherapies
Vinca alkaloids, taxanes, camptothecins, antibiotics and anthracyclines.
Example of selective oestrogen receptor modulator and use
Tamoxifen. In hormone-dependent breast cancer.
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.
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.
Use of selective oestrogen receptor modulator in post-menopausal women
Use with a gonadotropin releasing hormone analogue e.g. leuprolide to lower oestrogen production.
Excretion of Tamoxifen
in faeces.
Alternative, non-steroidal option for breast cancer (esp in post-menopausal women)
Aromatase inhibitors
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.
Example of aromatase inhibitors
Anastrozole and Letrozole
Treatment of prostate cancer
Antiandrogens. Androgen receptor antagonists. Flutamide, Bicalutamide and Cyproterone Non-steroidal. Bioavailable orally and excreted in the urine.
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.
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.
Oncogene in melanomas and targeted treatment
B-raf - a serine/threonine protein kinase. Inhibitors of b-raf used in melanoma treatment.
use of Raf inhibitors
Nexavar - renal cancer also has action on tyrosine kinase. b-raf inhibitors in melanoma.
Action of monoclonal antibodies
Prevent binding of growth factors to cell. Initiate an immune response on cell. Conjugated to a toxin or radioisotope.
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.
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.
Examples of monoclonal antibodies used
Herceptin/Trastuzumab, Rituximab, Bevacizumab and Cetuximab.
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
Herceptin/Trastuzumab administration, ADR
IV, can be given with other chemotherapy e.g. paclitaxel. ADR = heart failure.
Bevacizumab use and action
used in colorectal cancers. restrains the action of vascular endothelial growth factor A. Decrease angiogenesis.
Administration of Bevacizumab and ADR
Often with 5-Fluorouracil. IV. ADR = hypertension and interstitial bleeding.
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.
Administration and ADR of Rituximab
IV. can be given in combo with other chemotherapeutics e.g. cyclophosphamide. ADR: hypotension, fever, cardiac pathologies
Cetuximab use and action
Targets epithelial growth factor. Used in colorectal cancer treatment
Administration and ADRs of Cetuximab
IV in combo with irinotecan. ADR = fever, hypotension.
recombinant enzyme example
L-Asparaginase
Use of L-asparaginase
Childhood acute lymphocytic anaemia with prednisolone and vincristine. Used in tumours with low asparagine concs
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.
Two types of interferons
type 1 IFNs with alpha and beta and type 2 IFN with gamma.
Action of interferons
Promote apoptosis in cancer cells, stimulate immune recognition of cancer cells.
Use of interferons in cancer treatment
IFN-α2a and IFN-α2b - Interferon ALPHA. Used in Melanoma, renal cell carcinoma, Kaposi sarcoma HIV associated.
Administration of interferon alpha
IM, sub cut or IV.
Interleukins in cancer treatment
Interleukin 2 used in renal cell carcinoma and melanoma. Potentially interleukin-12 too
Action of interleukin 2
T lymphocyte growth factor. May act synergistically with IFNα2a.
ADR of interleukin 2 use
Hypotension, liver damage. REVERSIBLE. MAX dose of 14 due to tolerance.
Action of interleukin 12
Stimulates B and T cells and natural killer cells.
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.
