Test 3: 43 and 44: anticancer drugs Flashcards
3 hallmarks of cancer
unrestricted cell division
tissue invasion and metastasis
sustained angiogensis
S phase of cell cycle
DNA synthesis/replication
log kill hypothesis for cancer treatment
One round of chemotherapy:
kills a constant fraction of cells;
does not kill all tumor cells
what are some mechanisms for drug resistance in cancer cells
- Gene amplification
- Qualitative changes in drug target
- Enhanced DNA repair pathways
- Multi-drug resistance protein
- Increased pools of reduced glutathione (inactivate alkylating drugs)
P-glycoproteins on cancer cell membrane do what
push drug out of cancer cell
leads to multi drug resistance
goal of metronomic chemotherapy
desired endpoint for metronomic chemotherapy is stabilization of disease rather than an overall reduction or elimination of tumor
low dose cytotoxic drug given at regular intervals= less toxic and less expensive
Requirements for effective combination cancer therapy
- Drugs must be individually active
- Each drug must act via different mechanism
- Drugs should have different toxicities
- Intense intermittent schedules
what are some alkylating cancer drugs
derived from mustard gas
- Bis(chloroethyl)amines (Cyclophosphamide, chlorambucil)
- Ethylenimines
- Alkylsulfonates
- Nitrosoureas (Carmustine, semustine, lomustine)
- Platinum drugs (not true alkylators)
how do alkylating cancer drugs work
Add alkyl group radicals to DNA
– intra and inter strand Crosslink DNA at guanine (damage DNA)
leads to single and double stranded breaks → misreading of genetic code
interferes with DNA replication (S phase and transcription)
effects of DNA alkylation with cancer meds
- Intra and inter-strand crosslinking
- Single and double stranded breaks
- Misreading of genetic code
- Guanine depurination
Interferes with DNA replication -S phase & transcription -cell cycle non-specific (CCNS)
adverse effect of alkylating drugs
! Cytotoxic
! Immunosuppressive
! Infertility
! Nausea, vomiting (GI)
! Mutagenic
! Teratogenic
! Carcinogenic
how do cancer cells become resistant to alkylating drugs
increase glutathione- will bind to alkylating agents and prevent them from binding to DNA
increase DNA repair- remove cross links
decreased cellular permeability
Bis(chloroethyl)amines: Cyclophosphamide
alkylating anticancer drug derived from mustard gas
metabolized in liver to acrolein which is excreted in urine but can be bladder irritant
what is acrolein
byproduct of the breakdown of alkylating anticancer drug: Bis(chloroethyl)amines: Cyclophosphamide
acrolein irritates the bladder mucosa and can lead to hemorrhagic cystitis
negative effects can be reduced
w/ diuresis and increased water intake
chlorambucil
alkylating anticancer: Bis(chloroethyl)amine
slower acting than cyclophosphamide but does NOT cause hemorrhagic cystitis
can Bis(chloroethyl)amine anticancer drugs cross the BBB
no
can nitrosoureas anticancer drug cross the BBB
yes
carmustine, lomustine, semustine
how do nitrosoureas anticancer drugs work
prodrug: metabolized into Carbonium ions and Isocyanate
Carbonium ions- can alkyate nucleophiles and cause crosslinking of DNA
Isocyanate: Carbamylates proteins (inhibits protein function)
carmustine, lomustine, semustine
can cross BBB
how do platinum anticancer drugs work
act similar to alkylating agents
form crosslink DNA at guanine and cytosine
Interferes with DNA replication (S phase)
cisplatin, carboplatin
can cisplatin cross the BBB
no
platinum anticancer drug: acts like alkylating drugs: cause crosslink in DNA that interferes with DNA replication (S phase)
what will happen to cat if you give cisplatin
severe pulmonary toxicity
cisplatin: platinum anticancer drug: acts like alkylating drugs: cause crosslink in DNA that interferes with DNA replication (S phase), poor BBB penetration, builds up in kidney and liver
what are two types of anti metabolites anticancer drugs
folic acid antagonists
pyrimidine antagonists
how does methotrexate work
anticancer drug
folic acid analog
Competitively inhibits dihydrofolate reductase (DHFR)
– Inhibits DNA synthesis (indirect)
– Also interferes with RNA and protein synthesis
— converts folate to FH 2 (dihydrofolate)
and FH4 (tetrahydrofolate)
dihydrofolate reductase (DHFR)
FH4 is then used to make:
* thymidylate (dTMP)
* purine nucleotides
* methionine and serine amino acids
methotrexate- anticancer drug that competitively inhibits DHFR
can methotrexate get into brain
yes
methotrexate- anticancer drug that competitively inhibits DHFR
how to reverse toxicity of methotrexate
leucovorin (synthetic FH4)
methotrexate- anticancer drug that competitively inhibits DHFR
mechanism of methotrexate resistance
- Mutations in DHFR that lower affinity for MTX
- DHFR gene amplification
- Decreased drug transport
methotrexate- anticancer drug that competitively inhibits DHFR
— is a pyrimidine antagonist anticancer drug
Cytarabine (cytosine arabinoside; AraC)
prodrug- once activated cytotoxic to proliferating cell
Prevents DNA synthesis and inhibits DNA repair
how do vinca alkaloids work
derived from plant
binds to tubulin and disrupts microtubule structure (M phase)
promote microtubule disassembly
Vincristine, Vinblastine, Vinorelbine, Vinflunine
how do cancer cells develop resistance to vinca alkaloids
increase MDR1 (P-glycoprotein)
channel that pushes drug out of cancer cell
doxorubicin
anticancer antibiotics
Intercalating agent- Primarily blocks DNA synthesis (S phase)
slips inbetween DNA and forms complex that can not be unwound→ Inhibits topoisomerase II (Fragments DNA
3 activities of doxorubicin
DNA intercalation → leads to DNA breakage
generates Oxygen free radicals → helps break DNA, damaged cardiac cell membranes
alters fluidity of cell membrane
antibiotic anticancer med
adverse effects of doxorubicin
cumulative cardiac toxicity
tissue necrosis
hemorrhagic enteritis
antibiotic anticancer med- forms DNA intercalation which results in DNA breakage
actinomycin D will cause —
single stranded breaks in DNA
inhibits DNA and RNA synthesis
intercalates DNA between guanine-cytosine base pairs
antibiotic anticancer med
Bleomycin does not cause — like actinomycin D
myelosuppression
antibiotic anticancer med: binds to guanine base and forms bleomycin-Fe(II) DNA → free radical formation and DNA breakage
bleomycin cause cancer cells to accumulate in —
G2 phase
antibiotic anticancer med
how does bleomycin work
binds to guanine bases and form complex that cause release of free radicals
leads to DNA breaks
antibiotic anticancer med- no myelosuppression and cause cells to get stuck in G2 phase
adverse effects of bleomycin
lung toxicity and fibrosis
No significant myelosuppression (bone marrow sparing)(unlike actinomycin D)
antibiotic anticancer meds
