CHEMOTHERAPY DRUGS Flashcards
types of cancer treatment
surgery
radiation
chemotherapy
treatment will depend on the type of cancer, progression of the disease, health of the pt and pt choice
chemotherapy
the treatment of cancer with one or more cytotoxic drugs
often used in conjunction with other treatments (radiation therapy, surgery etc.)
most common side effects of chemotherapy
myelosuppression (decreased production of blood cells, hence also immunosuppression)
mucositis (inflammation of the lining of the digestive tract)
alopecia (hair loss)
chemotherapy moa
act by killing cells that divide rapidly, one of the main properties of cancer cells, this means that chemotherapy also harms cells that divide rapidly under normal circumstances: cells in the bone marrow, digestive tract and hair follicles
problems with chemotherapy
- treatments are non-specific, attack healthy cells as well as cancer cells
- cancers are heterogenous - genes mutated so bits of some cancers or metastases may be resistant to some drugs
indicators that the cancer has developed resistance to therapy
- decreased drug uptake/increased efflux
- enhanced tolerance of DNA adducts
- enhanced repair of DNA adducts
- increasing drug deactivation by intracellular glutathione
- toxicity to normal cells
types of anticancer drugs PATAAT
platinates
anthracyclines
taxanes
alkylators
antimetabolites
topoisomerase inhibitors
how do PATAAT drugs act
act by inducing cellular apoptosis (programmed cell death)
alkylation
transfer of an alkyl group from one molecule to another - alkylation of DNA is used in chemotherapy to damage the DNA of cancer cells
alkylating agents moa
attaches to an alkyl group (Cn H2n+1) to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring
consequences of alkylating agents
- DNA fragmented by repair enzymes in their attempts to replace the alkylated bases
- addition of the alkyl group to the base causes the mispairing of the nucleotides leading to mutations
- alkylating agents cause formation of cross-bridges, bonds between atoms in the DNA - 2 bases are linked together by an alkylating agent that has 2 DNA binding sites. cross-linking prevents DNA from being separated for synthesis or transcription. as this is necessary on DNA replication, the cells can no longer divide
6 groups of alkylating agents
nitrogen mustards
ethylamines
alkylsulfonates
triazenes
piperazines
nitrosureas
alkylating-like drugs: platinum-based drugs
CISPLATIN AND CARBOPLATIN
- platinum analogues act similarly to alkylating agents
- these agents do not have an alkyl group, but damage DNA
- they permanently coordinate to DNA to interfere with DNA repair
cisplatin effect on DNA
- replication inhibition
- transcription inhibition
- cell-cycle arrest
- DNA repair
- cell death
cisplatin side effects
- small therapeutic window
- neurotoxic (nerve damage) - visual perceptions, hearing disorders
- nephrotoxic - related to reactive oxygen species
- nausea and vomiting - often given with anti-emetics
- myelotoxicity - bone marrow suppression
carboplatin
- delivers the same drug as cisplatin but with chloride ligands replaced with bidentate dicarboxylate
- preferred first line with ovarian and small cell lung cancer
- takes less time to administer than cisplatin
- solution (10mg/ml)
satraplatin
- first platinum anti-cancer drug that can be administered orally
- most platinums are usually given in combination with other drugs
- indicated for prostate cancer
anthracycline-based drugs - intercalating drugs
- natural products derived from various strains of streptomyces bacteria
- four-ring structure linked via glycoside bond to daunosamine
- doxorubicin = for many solid tumours
anthracycline side effects
- nausea and vomiting, extravasation can cause tissue necrosis, bone marrow depression/immunosuppression, myelosuppression, infertility, dehydration
- myocardial toxicity from cumulative doses of around 450-500mg/m2 - patients need cardiac monitoring
- 1 in 2 patients in every 100 develop acute myelogenous leukaemia or myelodysplastic syndrome. risk even higher for those concurrently treated with cyclophosphamides or radiotherapy.
actionmycin D
- inhibits transcription
- it does this by binding DNA at the transcription initiation complex and preventing elongation of RNA chain by RNA polymerase
microtubules function
- cell shape
- cell movement
- movement of cargo within cell
- mitosis
spindle poisons
alters structure and function of microtubules
example of spindle poisons: vincristine, used for…
- acute leukaemia’s
- Hodgkin’s lymphoma
- non-Hodgkin’s lymphoma
- small cell lung cancer
adverse effect of vincristine
peripheral neuropathy
cisplatin structural effect on DNA
binds to DNA and causes a critical 45 degree bend
cisplatin
- indicated for metastatic testicular tumours, metastatic ovarian tumours and advanced bladder cancer
- small therapeutic window
dose-limiting toxicities
chemotherapy side effects severe enough to prevent giving more of the treatment. may result in treatment delay, dose reduction or discontinuation of treatment
carboplatin dose
IV 400mg/m2 over 15-60 minutes every 4 weeks
FOLFOX treatment
- indicated for colorectal cancer
- combination of oxaliplatin and fluorouracil and folinic acid
anthracycline drugs
doxorubicin
daunorubicin
idarubicin
doxorubicin moa
- attaches to DNA, distorting its double helical structure
- hydrophobic DNA base pairs interact with planar rings of doxorubicin
- inhibits topoisomerase II inducing DNA breaks
doxorubicin dose
IV 60-75mg/m2 every 21 days
doxorubicin side effects
- nausea/vomiting
- myelosuppression
- infertility
- dehydration
- myocardial toxicity
actinomycin D
- indicated for paediatric cancer
- no cardiotoxicity
vinca alkaloids
VINCRISTINE
VINBLASTINE
VINORELBINE
- inhibits mitosis of affected cells causing apoptosis
- bind to tubulin monomers keeping microtubules from forming
taxol
- indicated for ovarian/prostate/breast/head/neck cancer, non-small cell lung carcinoma, aids relayed Kaposi’s sarcoma, gastric adenocarcinoma
taxol side effects
hair loss
stomach issues
neutropenia (DLT)
taxols
PACLITAXEL
DOCETAXEL
paclitaxel moa
stabilises microtubules resulting in interference with normal breakdown of microtubules during cell division therefore cell cannot divide
antimetabolites moa
work via 2 methods:
- the antimetabolite gets incorporated instead of the normal metabolite (antimetabolites as competitive substrates)
- the antimetabolite inhibits the enzyme involved in the synthesis or reuptake of a metabolite (antimetabolites as enzyme inhibitors)
BOTH INDUCE CELLULAR APOPTOSIS
- many are nucleic acid analogues and can get incorporated into the DNA
anti-folates
methotrexate
hydroxyurea
anti-pyrimidines (pyrimidine analogues)
5-fluorouracil
cytarabin
anti-purines (purine analogues)
6-mercaptopurine
6-thioguanidine
purines and pyrimidines
PURINES (double ring): adenine and guanine
PYRIMIDINES (single ring): cytosine and thymine (uracil in RNA) needed for nucleic acid synthesis
de novo pathway
assembles nucleotides from amino acids and other small molecules
salvage pathway
recycle the free bases and nucleotides released from DNA breakdown
normal cells in nucleotide synthesis
- de novo pathway is inactive
- salvage pathway is dominant
cancer cells in nucleotide synthesis
- de novo pathway is active
- salvage pathway is inactive
mercaptopurine moa
prevents synthesis of guanosine monophosphate (dGMP)
mercaptopurine
- indicated for leukaemia
- liver toxicity, enzyme elevation, jaundice, cirrhosis
mercaptopurine side effects
- nephrotoxicity
- leucopenia
- vomiting
- myelosuppression
gemcitabine moa
- structurally similar to deoxycytidine (dCTP) so competes for incorporation into DNA
- nucleoside metabolic inhibitors kill cells undergoing DNA synthesis
- once incorporated into DNA chain can no longer be elongated causing cell apoptosis
- inhibits replication and repair
- inhibits enzyme ribonucleotide reductase - decreases deoxynucleotide concentrations
indications for gemcitabine
indicated for bladder/pancreatic/breast cancer
usual chemo toxic side effects
5-fluorouracil moa
antimetabolite
inhibits thymidine synthase
methotrexate moa
blocks the synthesis of folic acid by binding to dihydrofolate reductase and folic acid receptors on cancer cells which interferes with DNA synthesis/transcription
methotrexate
oral/IV/IM or intrathecally injected
folinic acid or folic acid given alongside to prevent side effects
methotrexate side effects
loss of appetite
nausea
GI discomfort
diarrhoea
hair loss
topoisomerase I inhibitors
irinotecan
topotecan
camptothecin
topoisomerase II inhibitors
etoposide
doxorubicin
epirubicin
topoisomerase inhibitors moa
- block the ligation step of cell cycle
- this generates single-/double- strand breaks leading to apoptosis
topoisomerase
binds to DNA molecules that are supercoiled
topoisomerase I
relaxes supercoiled DNA to remove helical constraints by cutting the double strand to make a single strand to allow room for a new DNA strand
topotecan
- indicated in ovarian cancer, small cell lung cancer
- really potent radiosensitiser and chemosensitiser
