clinical oncology Flashcards
cancer treatment: explain the main chemotherapeutic and targeted approaches to treating cancer, explain why many cancer treatments cause side effects and recall approaches to minimise this. Explain the rationale for developing new targets and new drugs in cancer therapy
4 main anti-cancer treatment modalities
surgery, radiotherapy, chemotherapy, immunotherapy
types of genetic mutations causing cancer (can be inherited)
chromosome translocation, gene amplification (copy number variation), point mutations within promoter or enhancer regions of genes, deletions or insertions, epigenetic alterations to gene expression
systemic chemotherapy: cytotoxic chemotherapy treatments
alkylating agents, antimetabolites, anthracyclines, vinca alkaloids and taxanes, topoisomerase inhibitors
systemic chemotherapy: targeted therapies
small molecule inhibitors, monoclonal antibodies
how do cytotoxics work
“select” rapidly dividing cells by targeting their structures (mostly the DNA)
what to alkylating agents, antimetabolites, anthracyclines and topoisomerase inhibitors target
DNA
what do vinca alkaloids and taxanes target
mitotic microtubules
how is cytotoxic chemotherapy administered
i.v. or occasionally orally
what does cytotoxic chemotherapy target
non targeted, so affects all rapidly dividing cells in body
4 occasions when cytotoxic chemotherapy given
post-op (adjuvant to destroy any remaining cancer cells), pre-op (neoadjuvant to downsize prior to surgery), as monotherapy or in combination, with curative or palliative intent
what do alkylating agents do to prevent DNA from uncoiling at replication
add alkyl groups to guanine residues in DNA, causing cross-linking (intra, inter, DNA-protein) between DNA strands and preventing DNA from uncoiling at replication
what do cells do when they can’t uncoil at replication following alkylating agent use
undergo apoptosis via checkpoint pathway
what do alkylating agents encourage
miss-pairing - oncogenic, but risk of relapse cancer (benefits>risk)
what do pseudo-alkylating agents add instead of an alkyl group to guanine
platinum (same mechanism of action)
3 examples of pseudo-alkylating agents
carboplatin, cisplatin, oxaliplatin
4 examples of alkylating agents
chlorambucil, cyclophosphamide, dacarbazine, temozolomide
9 side effects of alkylating and pseudo-alkylating agents
hair loss (not carboplatin), nephrotoxicity, neurotoxicity, ototoxicity (platinums), nausea, vomiting, diarrhoea, immunosuppression, tiredness
how do anti-metabolites cause apoptosis
masquerade as purine (adenine / guanine) or pyrimidine (thymine / uracil / cytosine) residues, or folate antagonists, leading to inhibition of DNA synthesis, DNA double strand breakage and apoptosis
what do anti-metabolites block
DNA replication and transcription
what do anti-metabolite folate antagonists do
inhibit dihydrofolate reductase, which is required to make folic acid (used in all nucleic acids, especially thymine)
7 examples of anti-metabolites
methotrexate (folate), 6-mercaptopurine, decarbazine and fludarabine (purine), 5-fluorouracil, capecitabine, gemcitabine (pyrimidine)
7 side effects of anti-metabolites
hair loss (alopecia; not 5FU or capecitabine); bone marrow suppression causing anaemia, neutropenia and thrombocytopenia; increased risk of neutropenic sepsis or bleeding; nausea and vomiting (dehydration); mucositis and diarrhoea; palmar-plantar erythrodysesthesia (PPE; red hand and feet with peeling skin); fatigue
3 things that anthracyclines do
inhibit transcription and replication by intercalating (inserting between) nucleotides within DNA/RNA strand, block DNA repair (mutagenic), create DNA and cell membrane damaging free oxygen radicals
2 examples of anthracyclines
doxorubicin, epirubicin
7 side effects of anthracyclines
cardiac toxicity (arrhythmias, heart failure due to free radical damage), alopecia (hair loss), neutropenia, nausea and vomiting, fatigue, skin changes, red urine
how do vinca alkaloids work
inhibit assembly of mitotic microtubules
how do taxanes work
inhibit disassembly of mitotic microtubules
what do vinca alkaloids and taxanes cause dividing cells to undergo
mitotic arrest
7 side effects of vinca alkaloids and taxanes
nerve damage (peripheral neuropathy, autonomic neuropathy), hair loss, nausea, vomiting, bone marrow suppresion (neuropenia, anaemia, thrombocytopenia), arthralgia (joint pain), allergy
2 things that topoisomerases do
prevent DNA torsional strain during replication and transcription by inducing temporary single strand (topo1) or double strand (topo2) breaks in the phosphodiester backbone of DNA; protect free ends of DNA from aberrant recombination events
cytotoxic chemotherapy drug which has anti-topoisomerase effects
anthracyclines
3 specific topoisomerase inhibitors which allow permanent DNA breaks
topotecan, irinotecan (topo1), etoposide (topo2)
4 side effects of topoisomerase inhibitors
hair loss, nausea and vomiting, fatigue, bone marrow suppression (anaemia, neutropenia, thrombocytopenia)
side effect of irinotecan (topo1)
acute cholinergic type syndrome, causing diarrhoea, abdominal cramps and diaphoresis (sweating)
what is irinotecan (topo1) given with to prevent acute cholinergic type syndrome
atropine
2 most important toxicities
bone marrow suppression, neutropenic sepsis (as vulnerable to infection due to neutropenia)
4 resistance mechanisms of cells to chemotherapy
enhanced DNA repair, remove DNA adducts by base excision repair (PARP), enhance ATP-binding cassette transporter on surface to efflux drug, heterogeneity of cells
monogenic vs polygenic treatments
can stop individual processes in monogenic cancers but for others, parallel pathways or feedback cascades are activated and upregulated
how do dual kinase inhibitors counteract polygenic upregulation, and disadvantage
block more pathways, preventing feedback loops but increases toxicities
10 hallmarks of cancer cell
self-sufficient, insensitive to anti-growth signals, anti-apoptotic, pro-invasive and metastatic, pro-angiogenic, non-senescent, avoid immune destruction, deregulate cellular energetics, genome instability and mutation, tumour-promoting inflammation
self-sufficiency of cancer cells
normal cells need growth signals to move from G0 to active proliferation (signals transmitted into cell via growth factors binding to receptors and causing downstream cascade), however cancer cells ignore as have not dismantled cell cycle machinery
3 examples of over-expression of receptors on cancer cells
HER2, which is amplified and over-expressed in 25% breast cancer; EGFR, which is over-expressed in breast and colorectal cancer; PDGFR, which is over-expressed in glioma
what does over-expression of receptors or ligands, or constitutive receptor activation, on cancer cells lead to
increased kinase cascade and signal amplification
example of over-expression of ligand for cancer cells
VEGF ligand, which is amplified and over-expressed in prostate, kidney and breast cancers
2 examples of constitutive (ligand independent) receptor activation
EGFR (lung cancer), FGFR (head and neck cancers, myeloma)
4 types of monoclonal antibodies
-momab (derived from mouse antibodies), -ximbab (chimeric), -zumab (humanised), -mumab (fully human)
humanised vs chimeric monoclonal antibodies
in humanised, murine regions interspersed withing light and heave chains of Fab portion, whereas in chimeric, murine component of Fab maintained integrally
what do monoclonal antibodies do
target EC component of receptors and neutralise ligands, which prevents receptor dimerisation and downstream signalling, or causes internalisation of receptor
how can monoclonal antibodies lead to an immune response
complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity
what receptor does cetuximab target
EGFR
what ligand does bevacizumab bind to and neutralise
VEGF
what do small molecule inhibitors do
bind to kinase domain of tyrosine kinase within cytoplasm, blocking autophosphorylation and downstream signalling
example of small molecule inhibitor and what it targeted
Gleevec (bcr-abl - Philadelphia chromosome), which targeted the ATP binding region within kinase domain
what is oncogene addiction, and why is this in treatment not always possible
where a cancerous cell creates a uniquely hyperactive oncogene driving a tumour, so can target but many caner cells don’t have it
besides receptor tyrosine kinases, what else can small molecule inhibitors act on
IC kinases, so affect signalling pathways
targeted therapies vs cytotoxics
by acting on EC or IC receptors, targeted therapies block cancer hallmarks without toxicity observed with cytotoxics
advantages of monoclonal antibodies
highly specific, generate immune response, long-lasting
advantages of small molecule inhibitors
can be ligand independent, oral administration, cheap, good tissue penetration
disadvantages of monoclonal antibodies
large structures so low tumour/BBB penetration, only useful if EC target, can cause allergy, usually i.v. administration
disadvantages of small molecule inhibitors
shorter half life, more frequent administration
main issue with all cancer chemotherapy
resistance
4 resistance mechanisms to targeted therapies
mutations in ATP-binding sites, intrinsic resistance, intragenic mutations, upregulation of downstream or parallel pathways
how do anti-sense oligonucleotides and RNAi work
block translation of specific mRNA
