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.