cytotoxic chemotherapy Flashcards
(26 cards)
what is cytotoxic chemotherapy, how does it work and what does it use
cell killing drug treatment, interferes with DNA synthesis and mitosis, uses chemical agents to destroy/control growth of cancer cells
examples of chemical agents
natural products, natural product derived/semi synthetic, natural product inspired, synthetic anti cancer/cytotoxic drugs
-different agents different mechanisms
-some damage cells DNA and some prevent dividing
why does chemo treat the whole body and what are the effects of that
so it can treat cancer cells that have escaped the primary tumour
chemotherapeutic drugs can distinguish between healthy and cancer so both is affected, toxicity to normal cells=side effects
chemotherapeutic agents show selectivity for cancer cells
normal tissue can repair and grow so injury caused by chemo is temporary
what are the components of nucleotide vs nucleoside
nucleotide=base+deoxyribose sugar+phosphate
nucleoside=base+deoxyribose sugar
what is the most susceptible to damage from alkylating agent attacks
N7 of guanine
name 3 alkylating agents
cyclophosphamide, nitrosourea derivatives, triazenes
how is cyclophosphamide used, what cancers can it treat, what the moa (how does it release toxicity), unwanted side effects?
-in combination/sequentially with other antineoplastic drugs
-treats solid and leukemic tumours (brain breast bladder cervix lung endometrium)
-requires biotransformation by cytochrome P450 3A4 to exert toxicity, cytochrome found in liver and converts cyclophosphamide to 4 hydroxy cyclophosphamide, «converted to phosphoramide mustard which is active alkylating species and crosslinks RNA and DNA
-acrolein, causes haemorrhagic cystitis
what does nitrosourea derivatives have activity against, what properties does it have, how does it work, what causes its antineoplastic and toxic effects
-activity against solid and non solid tumours
-lipophilic, allows it to cross blood brain barrier
-chloroethylates DNA leading to alkylation or DNA crosslinks causing cell cycle arrest and apoptosis
what is triazene, what does it do, what does it treat
-methylating agent, delivers N3 methyl group to DNA, methylates N3/7 and O6 on guanine, N3/7 repaired but O6 is most toxic lesion, responsible for antitumour effects
-standard care for glioblastoma multiforme, treats high grade gliomas, malignant melanoma, brain metastases
how does resistance (to temozolomide) arise
-repair of methylated DNA (O6-MeG) by methylguanine DNA methyl transferase (MGMT) gives resistance
(O6MeG is mutagenic lesion caused by chemotherapy drugs (like temozolomide ), drug kills cancer by introducing the lesion, MGMT repairs O6MeG by removing methyl group and repairs chemotherapy induced damage making it resistant)
what is crosslinking DNA and the 2 types
covalent bonds form bt two DNA strands, prevents replication and kills them
interstrand=bonds bt opposite strands of DNA=stops rep and transc
intrastrand-bonds within same strand=changes structure, blocks transc
what do alkylating agents do
-transfer alkyl group onto DNA (methyl or chloroethyl)
damages DNA in S phase, blocks DNA synthesis, S-G2 arrest, DNA single/double strand breaks and cross links the two
what is the cisplatin structure, its MOA, side effects and compare to carboplatin
Pt(NH3)2(Cl)2
MOA=crosslinks DNA causing interstrand and intrastrand GG, AG Pt adducts
preferred site=N7 guanine
adverse reactions=renal/gastrointestinal toxicity, peripheral neuropathy
carboplatin=less toxic to kidneys and nervous system=less nausea and vomiting
what do platinum agents do and 2 examples
-cisplatin and carboplatin
-crosslink DNA, the damage triggers cell cycle arrest and DNA repair mechanisms, fails initially then activates apoptosis, S cell cycle phase stopped
what are antimetabolites, what do they do and examples
chemicals structurally similar to folate or nucleobases, deplete DNA building blocks
-inhibit production of DNA building blocks in G1 cell cycle phase to prevent synthesis
-eg. antifolates, purine and pyrimidine antagonists
what is folate,what does it do and methotrexate and moa
folate=growth factor, provides C atoms for nucleotide in RNA/DNA synthesis
methotrexate=folate antagonist, inhibits folate dependent enzymes
-enters cell by folate receptors, binds DHFR, inhibits synthesis of FH4, cell cant make new purine and thymidine nucleotides, synthesis of DNA RNA blocked
what do purine and pyrimidine antagonists do
purine antagonist=inhibits production of A and G in DNA RNA
pyrimidine antagonist=block CT or CU in RNA
how do pyrimidine analogues work w examples
-5 fluorouracil (5FU) and capecitabine decrease biosynthesis of pyrimidines by inhibiting thymidylate synthase
-capecitabine converted to 5-fluorouralcil in cancer cells, 5FU cant be methylated by thymidylate synthase causing inhibition of enzyme and decreased production of thymine, 5FU incorporated into DNA/RNA leading to cytotoxicity
-gemcitabine=pyrimidine nucleoside, replaces cytidine (building block of nucleic acids) during DNA synth, targets RNR (ribonucleotide reductase)
eg=5FU and gemcitabine
name 2 purine antagonists and what they do
-mercaptopurine=adenine analogue
-thioguanine=synthetic guanine analogue, inhibits purine synthesis
what do antimicrotubule agents do and give 2 examples, eg1-disadvantages, moa, treats what, eg2-treats what, moa
-inhibits mitosis, blocks cycle during mitosis
-paralyses tubulin or microtubules
-microtubules allow segregation of chromosomes during mitosis
eg1. paclitaxel/taxanes
-limited supply and extraction
-semi synthetic
-stabilise microtubules and block breakdown of it
-stops cell cycle in G2/M phase and prevents cell dividing
-treats breast, ovarian, lung carcinomas
eg2. vinca alkaloids
-isolated from madagascan periwinkle
-teats leukaemia, lymphoma, melanoma, soft tissue sarcoma, neuroblastoma, breast, lung cancers
-moa=inhibits tubulin polymerisation, destabilises (depolymerises) microtubules, destroys mitotic spindles leaving cells stranded in mitosis
what is used to prevent each stage of cell cycle
G1=antimetabolites
S=alkylating/platinum agents
M=tubulin/microtubule poisins
cytotoxic chemotherapy limitations
-normal cells divide rapidly, if damaged=side effects
eg. hair follicles>alopecia, bone marrow>fewer blood cells, digestive tract>sores/inflammation
-dosing limiting toxicities
-lack of clinical efficacy
-drug resistance
clinical mechanisms of resistance
-decreased drug uptake (Cu pump)
-enhanced drug efflux
-altered target expression (upregulated transcription/overexp of DHFR)
-DNA repair (MGMT removing methyl thing, temozolomide resis)
-failure to activate drug (cytochrome P450, cyclophosphamide)
-metabolic drug inactivation (cytochrome P450, taxol)
-mutations/altered activity of drug target (tubulin)
what is combination chemotherapy, what moa does it need
combination chemotherapy=treatment with a number of agents/regimes simultaneously/sequentially with distinct mechanisms of actions:
-eradicate tumour cells
-prevent emergence of acquired resistance
-limit toxicities, spare normal cells
