B-34. Cancer chemotherapy II (alkylating agents)

Question 1

Alkylating agent drugs

Answer 1

1. Cyclophosphamide
2. Ifosfamide
3. Mechlorethamine
4. Cis-, Carbo-, Oxaliplatin
5. Procarbazine and dacarbazine
6. Bleomycin, Actinomycin D

Question 2

Alkylating drugs MOA

Answer 2

Alkylators transfer an alkyl group to DNA strands, forming covalent cross-links within and between DNA strands resulting in strand breakage, decreased cell proliferation and increased apoptosis. They are all cell cycle non-specific chemotherapeutic agents.

Question 3

Resistance mechanisms for alkylating drugs

Answer 3

• Decreased cellular drug uptake
• Increased DNA repair
  
  • Increased drug inactivation - as in by glutathione upregulation or aldehyde dehydrogenase activity

Question 4

Side effects of alkylating drugs

Answer 4

Side Effects of alkylating drugs: generally worse than anti-metabolites

• GI effects - nausea, vomit; use 5-HT3 atgs to treat
• Myelosuppression
• Reproductive effects - inhibited menstruation / spermatogenesis
• Hair loss
• Secondary malignancies - can occur even 5-10 yrs after tx; especially leukemias + lymphomas
• Oto- / Neurotoxicity
• Injection Reactions - inflammation at injection site

Question 5

• Cyclophosphamide (CP)
  • MOA?
  • Resistance?
  • Kinetics?
  • Side Effects?
  • Indication?

Answer 5

• Cyclophosphamide (CP)
  • MOA: prodrug metabolized by CYP450 → alkylates guanine bases → inter-/intrastrand cross-links
  • Resistance: increased glutathione via ↑ glutathione S-transferase conjugates CP; aldehyde dehydrogenase inactivates CP
    
    • can ↑ efficacy by co-admin of disulfiram (aldehyde DH inhibitor)
  • Kinetics: parenteral admin
  • Side Effects:
    
    • Pulmonary fibrosis
    • Hemorrhagic cystitis - in about 10%; via metabolite acrolein; co-admin with NAC or mesna
      
      • CP increases risk of high-grade transitional cell carcinoma + other bladder cancer
    • SIADH- may induce hyponatremia
    • Gonadotoxicity- both ovaries + testes; may → infertility / premature menopause
  • Indication:
    
    • Solid tumors - breast cc. (combo with 5-FU) and ovarian cc.
    • Childhood tumors - Wilms tumor, rhabdomyosarcoma, etc.
    • and lymphomas
    • RA- not first-line (MTX first, then others, then CP)

Question 6

Classic Alkylating Agents - mustard nitrogen derivatives drugs

Answer 6

• Classic Alkylating Agents - mustard nitrogen derivatives
  
  1. Cyclophosphamide
  2. Ifosfamide
  3. Mechlorethamine

Question 7

Ifosfamide info and side effects

Answer 7

Ifosfamide - similar to CP; can cause encephalopathy and hemorrhagic cystitis (always given with mesna)

Question 8

Mechlorethamine info

Answer 8

Mechlorethamine - prototype alkylating agent, no longer used; now scheduled as a chemical weapon… wonderful

Question 9

Platinum analog drugs

Answer 9

• Platinum Analogs
  
  1. Cis-, Carbo-, Oxaliplatin**

Question 10

Platinum analogs main MOA and indications

Answer 10

• MOA: Platinum binds guanine (on N7) + forms inter-/intrastrand cross-links → ↓ DNA synth / function.
• Indications: mainly solid tumors … NSCLC, SCLC, testicular, ovarian + bladder cc.

Question 11

Cisplatin side effects

Answer 11

Cisplatin

• Nephrotoxic- including ATN and vasoconstriction; prevent w/ hydration, mannitol, NAC
  
  • treat with amifostine, a thiophosphate that binds toxic free radical metabolites
• Neurotoxic- symmetrical peripheral neuropathy (stocking / glove dist.)
• Ototoxic- worst of -platins; affects outer hair cells → dose-dep. high frequency loss / tinnitus

Question 12

Carboplatin side effects

Answer 12

• Carboplatin
  
  • Less oto-/nephrotoxic; only high doses cause neurotoxicity!
  • Dose-limiting myelosuppression (worst -platin for bone marrow!)

Question 13

Oxaliplatin indication and side effects

Answer 13

Oxaliplatin

• Indication: specifically colorectal cancer, as well as other -platin solid tumor indications
• Ototoxicity / nephrotoxicity is rare, but can still cause peripheral neurotoxicity

Question 14

• Procarbazine
  
  • Given?
  • Indications?
  • Side effects

Answer 14

Procarbazine - given orally for brain tumors and lymphomas; can cause CNS toxicity

Question 15

• Dacarbazine
  
  • Given?
  • Indication?
  • Extra?

Answer 15

Dacarbazine - given parenterally in melanoma and Hodgkin lymphoma; not used much anymore

Question 16

Complex forming antibiotic drugs

Answer 16

Bleomycin and Actinomycin D

Question 17

• Bleomycin
  
  • MOA
  • Indication
  • Side effects

Answer 17

Bleomycin

• MOA: small peptide with DNA and iron-binding regions → binds DNA and chelates metal ions which react with oxygen to form superoxide + OH^- free radicals → single- and double-stranded DNA breaks
  
  • is specific to G2 phase of the cell cycle
• Indications:
  
  • Hematological cancers - Hodgkin (in combo with doxorubicin) and NHLs
  • Solid tumors - germ cell tumors and SCC of skin, cervix + vulva
• Side Effects:
  
  • Pulmonary toxicity, including pulmonitis; fatal in rare cases
  • Skin toxicity - rash, exfoliation, hyperpigmentation and atrophic striae

Question 18

• Actinomycin D
  
  • MOA
  • Indications
  • Side effects

Answer 18

• Actinomycin D
  
  • MOA: binds + intercalates DNA/RNA, specif. at transcription initiation complex → inhibits transcription
  • Indications: childhood tumors such as Wilms tumor, Ewing sarcoma and rhabdomyosarcoma
  • Side Effects: alopecia + myelosuppression