Chemotherapy: Cancer Flashcards
Chemotherapy generally a second choice in
cancer
(commonly as adjuvant, neoadjuvant)
more responsive to lymphomas, leukaemia, testicular
in general - cancer in old age
leukaemia - children
1st choice for solid tumour
Surgery
IV or oral ie. systemic delivery/absorption
‘Finds’ the cancer cells wherever they are
better in non-solid tumours
but normal cells also affected
Chemotherapy
more selective/target therapy towards tumour
Immuno therapy
Characteristics of cancer cell
1. Uncontrolled proliferation Cancer grows more and more!!!! Number increased!!! lose control signals 2. loss of function/differentiation 3. invasiveness 4. metastases
Molecular basis of chemotherapy: aim
to kills as many tumour cells as possible with each treatment
not to harm normal
Selective toxicity
Exploit differences between normal cells and cancer cells
But cancel cells are our own cells that are out of control
covalently bind to DNA and prevent replication
Alkylating agents
AFFECT THE DNA
modify DNA structure
covalent bonds, DNA helix X links intra- and inter strand, attach to free guanines at N6 on separated DNA strands, cannot act as template for new DN formation
Bifunctional - can crosslink - intra (strand cannot get out of alpha helical conformation-wont replicate) and inter-strand cross linking (two strand wont separate which they need for replication)
prevent the syn of DNA precursors
antimetabolites
AFFECT the DNA PRECURSOR
immune suppression, anti-cancer, psoriasis - methotrexate (folate antagonists)
pyrimidine and purine analogues
rem as: metabolite =precursor
prevent cell division
cytotoxic antibiotics
major classes of cytotoxic drugs
- Alkylating agents - cisplatin
- Antimetabolites - Fluorouracil (FU)
- Mitotic inhibitors - etoposide, taxoid, Vinca alkyloids
- antibiotics - mitomycin
- others - hydroxyurea
Most target DNA
mitotic spindle poisons
Inhibit MITOSIS
relative non-toxic cancer drug
Vinca alkyloids and related compounds
vin.. groups
bind to tubulin
arrest at metaphase
steroid
Hormones
GFs, oncogenes, cyclins and CDKs
promote cell cycle
TSG, CDK inhibitors
inhibit cell cycle
… are the guardians to check if cell damaged/needs repairing?
Restriction points
How do you deliver chemotherapy?
IV or oral
regular cycle - watch on pharmacokinetics
may be need for delay to allow normal cells to recover (but also a problem as tumours can also recover) - we do go down with cells we have got after each drug admin- may have residual leftover cancer cells
but later, patient cannot take any more chemotherapy - endpoint for their treatment intensify the drugs
Methods for assessing drug activity
- objective response in adv disease : CT scan, PET scan, smaller masses clinically
- improved - survival, progression free survival, QoL
- Adjuvant treatment
- Neoadjuvant
Add the chemotherapy after the surgery
(Chemotherapy mops up residual tumour cells)
improves survival (usually)
Adjuvant chemotherapy
highly targeted to the type of cancer - multiple drugs - used to prevent drug resistance
Give the patient chemotherapy before the surgery
if big tumour, shrink more, better chance of success in removing the whole mass in the surgery
Neoadjuvant
Toxic drugs that are anti-proliferative (stops cells growing both normal and cancerous), but doesn’t affect invasion nor metastasis
Cytotoxic agents
we have drugs that kills cells but do not have one for metastases or invasiveness
Cisplatin (nephrotoxic) used for testicular cancer in young men - not an alkylating agent - but acts like one - adds platinum rather than alkyl group to crosslink the DNA strands
platinum (pos) bind with Neg DNA
DNA are …. charged
neg
drug commonly used in CRC (pyrimidine analogues)
5-FU (Fluorouracil)
analogue of uridine(forms a RNA base)
inhibits DNA & RNA syn by getting metabolised itself
5-FU > FUMP (blocks RNA) +FdUMP (blocks DNA)
lethal synthesis - cannot base pair - single stranded - susceptible to attack/dies
intercalate and inhibit DNA/RNA syn
free radicals formation
antimitotic antibiotics
anthracyclines and non-anthracyclines
inhibits topoisomerase ii (unwind DNA)
inhibit mitochondria function
nausea, vomiting, myelosuppression and alopecia
etoposide
freeze microtubules
attack mitosis
effect In ovarian and drug resistant breast cancer
taxol
….. Metastases common
Liver
Chemotherapy
Systemic therapy
Chemotherapy won’t work at G0 phase
Work for S, M phase
Breast and bowel
routine neoadjuvant
For lung - not used routinely
alkylating agents
cisplatin
replication fork arrest and irreversible DNA breakage
cell cycle interruption
cell death
CPT 11 Irinotecan ‘plant alkaloid’
prevent lymphocyte proliferation
side-effects with long-term treatment
Glucocorticoids hormones
immunosuppressive
acute lymphoblastic leukaemia; lymphomas (Hodgkin’s and non-Hodgkin’s)
combination therapy
Glucocorticoids hormones(prednisolone)
Sex hormones and antagonists
Response of tumour to sex hormones
dependent on receptor expression
ER+ - growth dependent on oestrogen
block effect of oestrogen on tumour cells
Oestrogen
breast cancer
binds to ER
no gene transcription
side-effects (blood clots, endometrial changes)
Tamoxifen (anti-oestrogen)
Combine
Different mechanism of action
Dissimilar toxicity profile
Combination chemotherapy
Combine those with
Different mechanism of action
Synergistic or at least additive
Reduce risk of developing resistance
Dissimilar toxicity profile eg not both with neurotoxicity (cisplatin and taxane)
Give each to maximum tolerated dose
Hormonal drugs
Anti-oestrogen Tamoxifen, aromatase inhibitors for breast cancer
Gonadorelin analogue eg Goseralin (Zoladex)
Anti-androgen (CPA, flutamide) for prostate cancer
Systemic Therapy
Targeted drugs against
Epidermal growth factor receptor (EGFR) Gefitinib/Erlotinib
Vascular endothelial receptor (VEGF) Bevacizumab (Avastin)
Multiple targets sorafenib, sunitinib, etc
Systemic Therapy
CINV
Chemotherapy induced nausea and vomiting
Acute response: Peripheral Enterochromaffin cell Serotonin release Vagal afferent 5-HT3 receptors
Central
Brainstem
NK1 receptors
Substance P
Dorsal vagal complex
Area postrema
Systemic therapy invoves: chemotherapy, and … drugs
Hormonal
Anti-oestrogen Tamoxifen, aromatase inhibitors for breast cancer
Gonadorelin analogue eg Goseralin (Zoladex)
Anti-androgen (CPA, flutamide) for prostate cancer
Targeted drugs against
Epidermal growth factor receptor (EGFR) Gefitinib - better
Vascular endothelial receptor (VEGF) Bevacizumab (Avastin)
Multiple targets sorafenib, sunitinib, etc
The First PD-1 Inhibitor Proven to Significantly Improve Overall Survival vs. Docetaxel1
Nivolumab
Chemotherapy side-effects
MAIN
- Myelosuppression (bone marrow suppression)
- Alopecia (hair loss)
- Infection risk increased
- Nausea
