Alkylating Agents and Platinum Compounds

drugs that generate reactive electrophilic intermediates that react with nucleophilic groups on DNA and proteins

alkylating agents

which purine base in DNA is the most common site for alkylation

guanine N7

what produces DNA intra- and interstrand linkages and why are these the most effective anti-cancer drugs

bifunctional alkylating agents, cross links inhibit DNA replication and are NOT cell cycle specific

what are alkylating agents in terms of electron status

electrophiles (electron deficient)

what type of linking is the major source of toxicity

cross linking

why do alkylating agents cause lots of adverse effects

react with many other nucleophiles other than DNA bases

what can react with alkylating agents and lead to resistance in cells

glutathione

what phase of the cell cycle are cells most susceptible to alkylating agents

late G1 and S phase, BUT alkylating agents are considered non-cell cycle specific

which normal cell populations are more sensitive to DNA alkylation and why

bone marrow, gut, mucosa because they are rapidly proliferating

most severe toxicity of alkylation and where they arise most

incidence of second malignancies, most in bone marrow (leukemia)

side effects of all alkylators

-Myelosuppression

-Nausea and vomiting

-Carcinogenic and teratogenic

how does chlorambucil reduce reactivity of mechlorethamine

decrease nucleophilicity of nitrogen by adding aryl groups

how does cyclophosphamide reduce reactivity

prodrug strategy

active metabolite of cyclophosphamide and how is it created

phosphoramide mustard (PM), hydroxylation in the tumor cell

what hydroxylates cyclophosphamide into PM

hepatic cytochrome P450

what enzyme deactivates PM

aldehyde dehydrogenase (ALDH)

which alkylating agent is most useful and most commonly used

cyclophosphamide

side effects of cyclophosphamide

mild bone marrow toxicity, hemorrhagic cystitis

toxic byproduct of cyclophosphamide

acrolein

how is acrolein toxic

accumulates in urine and damages bladder mucosa

drug used to counteract acrolein accumulation

mesna

MOA of mesna

accumulates in urine, free thiol reacts with and inactivates acrolein metabolites

covalent crosslinkers but not alkylating agents

platinum drugs

what is the necessary geometry with leaving groups in platinum drugs

cis (not trans!)

what activates cisplatin

reversible hydrolysis

where does equilibrium favor aquo form of cisplatin and why does this matter

inside the cell (low chloride concentration), aquo form is highly reactive and a potent electrophile

where does aquo form primarily react

guanine N7 and adenine N7 in DNA

what types of cross links are created by platinum drugs

intrastrand due to bond lengths and angles

how does intrastrand cross linking impact DNA

severe geometrical constraints, sharp bend not readily repaired

highly effective agent for many solid tumors that requires activation to aquo form

cisplatin

dose limiting side effect of cisplatin

nephrotoxicity

other SEs of cisplatin

N/V, minimal bone marrow toxicity, peripheral neuropathy, ototoxicity

what part of glutathione causes resistance to cisplatin and why

thiols- more nucleophilic than DNA so thiols intercept the reactive intermediate of alkylating agents and the cancer cell is not damaged

increased expression of what enzyme catalyzes the reaction of glutathione with alkylating agents and leads to resistance

glutathione S-transferase (GST)