anti cancer agent Flashcards
3 main approaches to eliminate cancer:
the role of these depends on — and —
- Surgical excision (local)
- Radiotherapy (local/regional)
- Chemotherapy (systemic/targeted) - Chemotherapy - increasingly used in combination
with surgery or radiation.
type n stage of development
in chemo:
— inhibit the proliferation of
dividing cells , but kill normal, rapidly proliferating cells also, e.g. bone marrow, GI mucosa, etc
cytotoxic drugs
classes of cytotoxic drugs:
- Antimetabolites
- Alkylating agents
- Cytotoxic antibiotics
- Plant alkaloids/microtubule inhibitors
1- antimatobilites;
* Structurally related to endogenous
compounds involved in —
* Act by — , — or — metabolic pathways in the biosynthesis of
DNA/RNA
examples:
(A). Folate antagonists (FA)
(B). Nucleic acid synthesis inhibitors
nucleic acids ( dna , rna ) synthesis
competition, block or subvert
a. folate antagonist FA
folate metabolism by which folate is essential for synthesis of —- and — which are both essential for — and —
purine nucleotides (Guanine & Adenine) and thymidylate
both essential for DNA synthesis and cell division
( folate → dihydrofolate (DHF) → tetrahydrofolate(THF)
↔ methylene-THF → methyl-THF → purine biosynthesis)
— is the most common widely used FA drug
* Acts by inhibiting the metabolism of –
* Inhibits — aka the enzyme which converts folates to tetrahydrofolate
* Affinity of MTX for DHFR is about — that of folate for DHFR
* Maximal effects are — specific
Methotrexate (MTX)
folic acid
dihydrofolate reductase (DHFR)
one thousand
s phase
b. Nucleic Acid Synthesis Inhibitors:
* — of purines/pyrimidines
– Inhibit enzymes either — or after — of a further false compound
– Form a — or — which is unable or slower to replicate due to extra binding groups
* — analogues: 6-thioguanine, 6-mercaptopurine
* —- analogues: 5-fluorouracil (5-FU),capecitabine, cytarabine (ara-C)
analogues
directly or after formation
false rna or dna
purine
pyrimidine
Widely used, particularly for colorectal cancer —
Fluorouracil (5-FU)
- 5-FU exerts its anticancer effects through:
- inhibition of —
- incorporation of its metabolites into –
- 5-FU is converted to several active metabolites including —-
- 5FU metabolised extensively in — , —
- 5FU prodrugs developed for – administration as — activated by cascade of 3 enzymes into 5FU
thymidylate synthase (TS)
rna n dna
Fluoro-deoxyuridine monophosphate (FdUMP)
gut n liver
oral
Capecitabine
( check slide 16 pls)
- alkylating agents :
Form —with DNA thereby inhibiting — during — and interfering with —
* Contain — groups (CnH2n+1) which have the property of forming covalent bonds with — in the cell
* Form — bond on — residues on same or adjacent strands
covenant bonds
dna synthesis
s phase
transcription
alkyl
nucleic acid
irreversible
guanin
( check slide 18 )
- Cause both intra and inter chain
linking - Main action occurs during
replication when some parts of DNA
are unpaired and therefore more
susceptible to –
alkylation
alkylating agent examples:
1- —- derivatives of mustard gas ( WW 1 , II )
- examples : Cyclophosphamide & ifosfamide
- forms —-
- is a — activated in — by —
2- —- as Carmustine [BCNU (bis-chloronitrosourea)]
– Causes alkylation of DNA and form – adducts with proteins
– Can pass — used in the treatment of several types of brain tumours, myelomas and Hodgkin’s lymphoma
3- —- as cisplatin which is a MOA analogue to alkylating agent )
* — complexes react in vivo, binding to and causing — of DNA which ultimately triggers —
* Revolutionised treatment of solid tumours of testes & ovary
* BUT seriously nephrotoxic, peripheral sensory neuropathy, resistance a problem.
* — and — (derivatives) - vastly reduced side-effects
nitrogen mustards
bifunctional dna adducts
prodrugs
liver
CYP450s
nitrosoureas
carbamoyl
BBB
alkylating-like
platinum
crosslinling
apoptosis
carboplatin n oxaliplatin
- cytotoxic antibiotics:
* Substances of — origin which prevent mammalian cell division
* — molecules which interpose themselves between the coils of DNA strands ( aka — ) and cause inhibition of —- biosynthesis
microbial
flat
intercalation
macromolecular
Anthracyclines as — are examples of –
doxorubicin
cytotoxic antibiotics
in cytotoxic antibiotics:
* Interacts with DNA by — and prevents correct — and exposure of DNA by stabilising — complex.
* Topoisomerase II relaxes supercoils in DNA for transcription.
* Used to treat — , — and — tumours.
* Adverse effect: —
− Produces — which are normally inactivated by:
1. Catalase ( – concentration in heart)
2. Glutathione peroxidase (inhibited by— )
intercalation
uncoiling
DNA- topoisomerase II
leukaemia lymphoma n solid tumours
cumulative cardiac toxicity
02 radicals
low
doxorubicin
dna topoiosmerases:
* Manage the — state of DNA in a cell, due to the double helical nature of DNA
* Create — in DNA, thereby allowing the DNA to ‘ – ’ around the helical axis and releasing torsional strain within the area before – the break.
* Two classes of this enzyme:
– topoisomerase I (topo I) functions by breaking just — DNA
– topoisomerase II (topo II) results in a —
topological
temporary strap breaks
swivel
resealing
one strand
double;e strand break
A. Vinca alkaloids
B. Taxanes
* Of plant origin
* Act on tubulin/microtubule dynamics
are:
Plant Alkaloids/Microtubule Inhibitors
Vinca alkaloids is a —
* —- : vincristine and vinblastine
* Act by binding to – and inhibiting its — into microtubules
* Prevent – formation and cause arrest at — during mitosis
plant alkaloids
spindle poisons
tublin
polymerisation
spindle
metaphase
taxanes are —
* — : derivative of yew tree bark
* — : semi-synthetic analogue of
paclitaxel
* Interferes with — by promoting formation of – and preventing— of formed microtubules during–
plant alkaloids
Paclitaxel (Taxol)
docetaxel
mitosis
intracellular microtubu;es
disassembly
anaphase
- — most common cause of failed
therapy - Drug treatment itself is a strong –
- Resistance to cytotoxic drugs may be:
– —: present when the drug is first given
– — : developed during treatment with the drug
resistance
selective pressure
primary
acquired
- Acquired resistance may be due either to — of the tumour cells or to –
- Leads to emergence of cells which are less affected or unaffected by the drug
- — over the sensitive cells
adaptation
mutation
selective advantage
mechanims of drug resistance:
1. — in amount of drug taken up by cell (e.g. — )
2. Insufficient — of drug ( – not
converted to — metabolite FdUMP* which inhibits — synthase)
3. — concentration of target enzyme (methotrexate: increased dihydrofolate reductase)
4. Increased — of alternative metabolic pathways (— )
5. – of drug induced lesion ( —
agents)
decreased
methotrexate
activation
FFU
active
thymidylate
increased
ultilization
repair
antimetabolites
alkhating agents
multi drug resistance MDR:
* Exhibit — resistance to many structurally — anticancer drugs (e.g. anthracyclines, taxanes, vinca alkaloids).
* MDR results from — of drug transporters : - ATP-binding cassette (ABC) transporter proteins
* P-glycoprotein (coded for by the mdr-1 gene)
- Mechanism of action:
– – accumulation of drugs in cells due to the increased — of a cell surface, energy-dependent, drug transport protein, termed P-
glycoprotein
elevated expression
decreased
expression
simultaneous
dissimilar
increased expression
decreased
increased expression
Schematic of P-glycoprotein Drug Transport Molecule
* Membrane transporter that
acts as a —
* — is used to drive the efflux
process
* — role thought to be the
protection of cells against environmental oxins
drug efflux pump
atp
physiological
( check slide 33,36)
summary of cytotixc drugs:
1. —-
A. Folate antagonists e.g. methotrexate
B. Nucleic acid synthesis inhibitors
– Purine analogues: 6-thioguanine, 6-mercaptopurine
– Pyrimidine analogues: 5-fluorouracil (5-FU), capecitabine, cytarabine (ara-C)
- A. Nitrogen mustards cyclophosphamide & ifosfamide
B. Nitrosoureas e.g. carmustine
C. Alkylating-like: cisplatin - A. Anthracyclines e.g.doxorubicin
- A. Vinca alkaloids e.g. vincristine and vinblastine
B. Taxanes e.g. paclitaxel and docetaxel
antimetabolites
alkylating agents
cytotoxic antbiotcs
Plant alkaloids/microtubule inhibitors