Intracellular Poisons: Alkylators

Question 1

Leaving groups are

Answer 1

electrophiles that are happy to take pair of electrons

Question 2

materials with electron density to spare

Answer 2

nucleophiles

Question 3

Biologic molecules are loaded with ____________ that have ______ that react with electrophiles

Answer 3

Biologic molecules are loaded with Sulfur, Nitrogen and Oxygen atoms that have lone pairs of electrons that can react with Electrophiles:

Question 4

Many drugs work by a mechanism involving

Answer 4

a highly reactive Electrophile which is generated (or unveiled) in a context that covalently (often irreversibly) alters a protein or nucleic acid.

Question 5

Alkylation

Answer 5

X-R(3)

Nu comes in and kicks of x leaving Nu-R(3)

Question 6

acylation

Answer 6

R1-C=O-x
Nu comes in and kicks out X
R1-C=O-nu

Question 7

mustards

Answer 7

2 cl and a middle N or S

Question 8

what do mustards like to attack and how

Answer 8

N(7) on guanine (-G-G-C-)

S or N get rid of Cl, reactive intermediate, and attack N(7) guanine = crosslink

Question 9

N7 is the most important

Answer 9

nucleophilic sites on DNA

Question 10

As usual, the electron rich stuff combines with the electron poor. In medicine, biomolecules (proteins, nucleic acids and glutathione) are ____________ and and drugs are the ________

Answer 10

As usual, the electron rich stuff combines with the electron poor. In medicine, biomolecules (proteins, nucleic acids and glutathione) are electron rich, and drugs are the electrophiles.

Question 11

DNA is usually ________ on N(7) of Guanine and this leads to breakage ________

Answer 11

DNA is usually alkylated on N(7) of Guanine and this leads to breakage of the “glycosidic” bond (i.e. base—sugar).

Question 12

_______ agents are more effective at creating lesions that are difficult to repair

Answer 12

bifunctional agents

Question 13

5 important Alkylators

Answer 13

cyclophosphamide
Bendamustine
Temozolomide
Cisplatin
Carboplatin

Question 14

Bendamustin
invented for
use for
SE

Answer 14

CLL
indolent B-cell malignanices
prolonged neutropenia in some patients

Question 15

cyclophosphamide
invented for 
oxidized by
metabolism
used for

Answer 15

originally made for GI cancers
cyto P-450, ALDH (good TI)
hematologic malignancies (CHOP), Wilm’s, Breast cancer, Germ cell tumors, autoimmune disease

Question 16

most potently immunosuppressive mustard

Answer 16

cyclophosphamide

Question 17

long-term administration, especially orally, of cyclophosphamide is associated with

Answer 17

induction of hemorrhagic cystitis, bladder cancer and myelodysplasia (especially 5q-)

d/t acrolein being toxic to lining of bladder

Question 18

what is a powerful inducer of G-CSF (and GM-CSF) and is often used to mobilize stem cells for collection by apheresis

Answer 18

cyclophosphamide

Question 19

what causes hemorrhagic cystitis, bladder cancer and myelodysplasia (especially 5q-)

Answer 19

long term admin of cyclophosphamide

Question 20

drug given w/ cyclophosphamide

Answer 20

Mercapto-ethylsulphonic acid, NA salt

MESNa

Question 21

MESNA

Answer 21

nucleophilic drug to soak up the acrolein, especially in the bladder.
(cyclophosphamide)

Question 22

More people get what than any other cytotoxic drug

Answer 22

cyclophosphamide

Question 23

what makes mustards useful for high-dose chemo w/ stem cell rescue

Answer 23

broad TI w/o obvious ceiling

Question 24

downsides of mustards

Answer 24

hemorrhagic cystitis, bladder cancer, myelodysplasia

Question 25

important mustard drugs

Answer 25

cyclophosphamide bendamustine chlorambucil melphalan ifosfamide

Question 26

important platinum drugs

Answer 26

cisplatin carboplatin oxaliplatin

Question 27

consequences of DNA adducts

Answer 27

Inhibition of transcription Inhibition of DNA replication Induction of apoptosis

Question 28

Cisplatin good for not very _____

Answer 28

indispensible for germ cell tumors | not very myelosuppressive

Question 29

cisplatin toxicities

Answer 29

Damage to VIIIth nerve, and long sensory nerves Kidney damage, often irreversible, manifesting as electrolyte wasting and ATN Nausea and Vomiting

Question 30

``` carboplatin good for not as active for pros myelosuppressive? ```

Answer 30

Great for solid tumors and salvage lymphoma regimes not as active as cisplatin in germ cell tumors, bladder, head and neck tumors - equivalent for Lung, gyn, and breast cancers much less neurotoxic, emetogenic, nephrotoxic than cisplatin quite myelosuppressive - thrombocytopenia

Question 31

_____ is unmatched in broad-spectrum anti-cancer activity, and unmatched in toxicity among clinically useful anticancer drugs

Answer 31

Cisplatin

Question 32

_______ is the most important toxicity (now that nephrotoxicity can be managed) of cisplatin

Answer 32

neuropathy

Question 33

________ clearly has the most favorable therapeutic index of platinum drugs

Answer 33

carboplatin

Question 34

_________ is active in GI adenocarcinomas, but is a very hard drug to take at extremes of latitude

Answer 34

oxaliplatin

Question 35

progenitors of diazomethane

Answer 35

dacarbazine, procarbazine Temozolomide

Question 36

Temozolomide is a prodrug for

Answer 36

MTIC

Question 37

Temozolomide good for

Answer 37

CNS tumors

Question 38

expression of ___ predicts poor clinical response to temozolomide

Answer 38

methylguanine methyltransferase (MGMT)

Question 39

non-classical alkylators mostly used for

Answer 39

gliomas

Question 40

Profound hematologic stem cell toxicity makes what useful for bone marrow transplant conditioning regimens

Answer 40

non-classical alkylators

Question 41

The ________ are vessicants, extremely emetogenic and seldom used

Answer 41

carbazines

Question 42

The dacarbazine-related prodrug ____________ is the current standard for glioma.

Answer 42

temozolomide

Question 43

Expression of MGMT, or MMR deficiency, circumvent toxicity from the methylation from what drug

Answer 43

temozolomide