Chapter 8 anticancer drugs - DNA alkylating agents + antimetabolites

Question 1

Mechlorethamine
chlorambucil (leukeran)
melphalan (alkeran)
cyclophosphamide (cytoxan)
ifosfamide (Ilex)
[nitrogen mustards] —- MC MCI
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carmustine (BCNU)
lomustine (CCNU)
streptozotocin (zanosar)
[nitrosureas] —- CLS
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Busulfan (myleran)
thiotepa
altreamine (hexalen)
temozolomide (temodar)
daarbazine (DTIC-dome)
procarbazine (matulane)
[other chemical classes] — BTA TDP

DNA alkylating agents

Answer 1

• Alkylate DNA — prevent DNA transcription (affects multiple phases of cell cycle)
• Erythropoietic and leukopoietic cells (blood cell precursors) , cell linings of GI, and hair follices — rapidly regeneration (susceptible to these akylating agents)

side effects as a result:
* anemia
* low platelets
* impair immune fx
* hair loss
* nausea
* gut toxicity

For nitrogen mustards,
* cyclophosphamide and ifosfamide (pro drugs that are inactive => become active in liver) => mesna given with cyclophosphamidie [can cause hemorrhagic cystitis (bladder) d/t toxic metabolite, which mesna binds to]

d/t resistance to alkylating agents ==> better to give altretamine [less cross resistance]

cancer cells make resistance via reduced uptake or repairing DNA

Question 2

methotrexate

antimetabolite

Answer 2

• blocks folate reduction by inhibiting dihydrofolate reductase (reduces dihydrofolate to tetrafolate, coenzyme needed for thymidylate production — essential precursor for DNA biosynthesis
• S-phase specific (prevent them from entering), arrests some cells in g1
• resistance — reduced uptake, gene amplifciation (more dihydrofolate reductase)

effects
* usual toxicity (dec blood cell count, nausea, hair loss)
* liver and kidney toxicity
* HIGHER doses monitored to ensure pt clears drug
* IF above threshold, can cause organ damage (leucovorin (formyl folate) given to save non cancerous cells)

• leucovorin — can restore folate stores in non cancerous cells

methotrexate used for RA, psoriasis (rash with itchy, scaly patches, most commonly on the knees, elbows, trunk and scalp, other autoimmune d/o’s [cytotoxic effects]

Question 3

Mercaptopurine (6-MP)
Thioguanine (6-TG)

purine analogs

Answer 3

6-MP metabolized to ribose phosphate derivative (6MPRP) that mimics negative feedback inhibitor to stop purine production in cells
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6-TG metabolized to Thio GTP or Thio dGTP which are placed into DNA where they block DNA repair or maintenance

• both cells s-phase specific

resistance:
* inc alkaline phophatase (breakdown of 6MPRP)
* decreased sensitivity to feedback inhibition
* decreased HGPRT (enzme that metabolizes these drugs)

effects
* decreased blood count
* nausea
* hair loss
* liver damage
* DOSES reduced if liver damage enzymes inc in blood

Question 4

claldribine (leustatin)

purine analog

Answer 4

• metabolized intracellularly => 2CdATP, which inhibits repair of single strand DNA + incorporates into DNA of dividing ells
• this metabolizing enzyme from cancer cells (deoxynucleotide deaminase - dATP specific) is reduced in non cancerous monocytes and lymphocytes => allowing cancer cells to be targeted
• overall – inhibits DNA repair (non phase specific) and inhibits DNA synthesis (s-phase) [blocks ribonucleotide reductase needed for DNA synthesis]

resistance:
* High levels of deoxynucleotide deaminase (redirected into non toxic pathways)
* Low levels of enzymes that make 2-CdATP

effects
* low blood count
* nausea
* hair loss

Question 5

Pentostatin (nipent)

purine analog

Answer 5

• inhibits adenosine deaminase l/t increased dATP
• function – blocks ribonucleotide reductase needed for DNA synthesis (s phase)

effects
* decreased blood cell count
* hair loss
* nausea
* liver damage

Question 6

fludarabine (fludara)

purne analog

Answer 6

• metabolized to 2-fluoro-ara-ATP; inhibits DNA polymerase, primase, and ribonuelotide reductase

effects
* dec blood cell count
* nausea
* hair loss

Question 7

5-flurouracil
floxuridine
capecitabine (xeloda)

pyrimidine analog

Answer 7

• metabolized to fluro-UMP, which incorporates into RNA
• also to fluro-dUMP that inhibits thymidylate synthetase (essential precursor for DNA biosynthesis)
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• floxuridine and capecitabine (both on left) convert to fluorouracil (since both are prodrugs)
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  all are s + g1 phase-specific

resistance
* dec phosphorylation of prodrug => active
* inc catabolism
* inc or altered target enzyme

effects
* low blood count
* nausea
* hair loss

Question 8

cytarabine

pyrimidine analog

Answer 8

• metabolized to ara-CTP, incorporated into DNA
• acts as chain terminator and inhibits polymerase
• s-phase specific!!!

Resistance:
* catabolism inc
* inc or altered target enzyme

SE
* nausea
* hair loss
* low blood count

Question 9

gemcitabine (gemzar)

pyrimidine analog

Answer 9

• phosphorylated to dFdCDP and dFdCTP => which both stop ribonucleotide reductase + DNA strand terminator
• s phase specific

Resistance:
* inc catabolism
* altered target enzyme or inc

SE
* nausea
* hair loss
* low blood count