nucleic acid based cancer therapies 1 and 2

what is the basis for anti cancer drugs selective drug toxicity to tumor cells?

difference in growth rate of populations, as they are in the S phase longer. they may also have reduce ability to repair cell damage resulting in apoptosis of cells. some agents have a preferance for GC rich areas.

what tumor reperssor gene will result in apoptosis if a cell is too damaged

p53

what are the 4 common side effects of chemotheapy?

alopecia, GI toxicity, naseua/vomiting, myelosupression

what molecules in DNA are targets for anticancer drugs ?

N7, 06, and N2 in guanine

what is the MOA of methylating agents?

They carry out electrophilic attack on the N7 O6 of guanine in the major groove, forming and adduct which prevents dna transcription and replication. it can also form a kink, which causes cell apoptosis.

what is an examples of a methylating agent?

darcarbazine

describe how dacarbazine generate the methlate ion?

prodrug, that is broken down by enzyme inside the cell to form the metholate ion

what methylating agent has good CNS penetration?

temozolomide ( used to treat brain cancer)

what does temozolomide( methylating agent) activity depend on, unique to other methylating agents.

MMR enzymes and a low expression of MGMT enzymes

How do MMR enzymes cause cell death to a methylated DNA

mismatch repair enzymes(MMR). when they come across a methylated guanine, they are tricked into thinking it is a adeonine. as a result they replace the cytosiene in the strand to a thymine, which causes a kink in the dna, which causes the strand to break.

How have repair proteins in our body evolved to overcome methylated DNA, resulting in the resistance to these treatments

through repair proteins like MGMT

what are two levels that px recieving temozolomide are screened for?

high MMR and low MGMT

what is the moa of alkylating agents?

alkylate the n2 of guanine in the minor groove that bends the DNA towards its binding site, forming a bulky adduct that interferes with DNA processing.

what is an example of an alkyalting agent?

ET 743

what does ET-743(alkyating agent) treat

breast, colon, lung, prostate ( major 4)

what is the mechanism of alkylation of nitrogen mustards

cross linking agent

describe the moa of cross linking for nitrogen mustards

Cl- undergoes cyclosation, which reacts readily with N7 in the major groove. this process repeats with the other Cl moeity, on a second guanine N7 from the other strand forming an interstrand crosslink, locking the DNA strands together which inteferes with DNA processing

what is an example of an aromatic nitrogen mustard?

melphalan

what type of anticancer agent is mitomycin?

cross linking agent

how is mitomycin selective for cancer cells?

requires enzymatic reduction that occurs in the hypoxic core of the tumor to cross link DNA

what is mytomycin used to treat?

upper GI and breast cancers

what is the MOA of nitrosoureas(crosslinking agents)?

decompose in the body to form chloroethyl carbonium ion which alkylates DNA, forming interstrand crosslinks.

what are nitrosoureas used to treat?

breast, lung and colon cancer and brain( high lipohilicity)

what is an example of an oral nitrosurea?

lomustine

what is the MOA of cisplatin( crosslinking agent)

interacts with major groove of DNA forming intrastrand crosslink at guanine N7

why does cis platin work really well in testicular cancer

germ cells have limited ability to repair the adducts so will apoptosis

in addition to normal side effects what are some SE that may be caused with cisplatin

periperhal nueropathy and ototoxicity

what is cisplatin used to treat

ovarian,lung, testicular,

what cisplatin drug is used to treat colorectal cancer?

oxaliplatin

what are the possible MOA of intercalating agents like anthracyclines?

wedge themselves in between the DNA base pairs and are stabilised by hydrogen and waan der valls interactions. this interferes with DNA processing.

they can also from complexes with topoisomerase enzymes and DNA which casues strands to break.

also effect the fluidity of the membrane which impacts the ion channels in the cell leading to cell death

what is an example of an anthracycline?

Doxorubicin

what is the MOA of topoisomerase 1 inhibitors?

keep the chromosomes wound tight so cell is unable to make proteins

what is an example of a topoisomerase 1 inhibitors?

ironotecan

what is the MOA of topoisomerase 2 inhibitors?

generate double-strand breaks, which blocks transcription and translation

what is an example of a topoisomerase 2 inhibitors

etoposide

what is the MOA of DNA cleaving agents?

bind and cleave the double stranded helix through radical production

what is an example of DNA cleaving agents

bleomycin

what anthracyline can be given orally and iv?

idarubicin

what is the only anthracene example?

mitoxantrone

what is bleomycin mainly used to treat and why?

head, neck and genitalia tumors as it accumulates in the squamous cells

what are some common toxicities associated with bleomycin?

skin, mucosa and lungs

at what interval is doxorubicin usually given?

21 day interval

how is doxorubicin excreted?

by the biliary tract

why can intercalating agents not be given alongside radiotherapy?

they are radio mimetics so mimic the effect of radiation which may lead to toxicity