Parang IE 1 Pharmacist Alerts

How to reduce skin toxicity of alkylating agents like mechlorethamine ?

• 2% sodium thiosulfate → mechlorethamine inactivation 

• Creates inactive, highly ionized, and water soluble thiosulfate ester that can be washed away

Which of the alkylating agents is used orally and why?

1. Nitrogen mustard

• Cyclophosphamide

• Non-toxic prodrug 

• High oral absorption and activation in the liver → GI toxicity and less nonspecific toxicity 

2. Aromatic nitrogen mustards 

• Chlorambucil 

  • Aromatic mustard 

  • Good oral bioavailability is less reactive alkylating agent & less side reactions/toxicity

•  Melphalan & Uracil mustard 

3. Nitrosourea 

• Lomustine 

  • Stable for oral use & capsule formulation 

which of the alkylating agents are oral ?

Cyclophosphamide

Chlorambucil

Melphalan

Uracil mustard

Lomustine

Why does cyclophosphamide cause bladder toxicity and how can we block the bladder toxicity of cyclophosphamide?

• Accumulation of Acrolein (highly active- forms covalent bonds with cysteine residues of essential proteins) 

• Mesna (cytoprotective agent) can be used to reduce toxicity 

  • Chemically reacts with toxic metabolite 

  • Reduces risk of hemorrhagic cystitis associated with high dose cyclophosphamide

Produces acrolein (haemorrhagic cystitis), detoxify bladder toxicity with mesna

Which of the agents are prodrugs and how are they activated?

1. Cylophosphamide 

   1. Metabolic activation in the liver mediated by CYP450  

   2. Lowered GI toxicity and less non-specific toxicity 

2. Dacarbazine

   1. Activated by demethylation in the liver 

   2. Decomposes to form a methyldiazonium ion then alkylates guanine groups 

3. Mitomycin C 

   1. Activated to form alkylating agent 

   2. One of the most toxic anticancer drug in clinical use 

4. Cisplatin 

   1. Activated in cells with low chloride ion concentration 

   2. Chloro substituents are replaced with neutral water ligans 

   3. Produces positivity charged species that react with DNA 

   4. Highly nephrotoxic 

   5. Give amifostine 

5. Amifostine

   1. Converted by alkaline phosphatase (AP) to active thiol with free SH group 

which of the agents are prodrugs in alkylating lecture?

Cyclophosphamide

Dacarbazine

Mitomycin C

Cisplatin

Amifostine

• How to improve the selectivity of antimetabolites to tumors? 

• Enzyme activated prodrugs (only become active when cleaved by an enzyme) ex. Capecitabine

• Overexpression of thymidine phosphorylase enzyme (much more active in tumors than normal tissue)

• How does rescue therapy work in methotrexate toxicity? 

Leucovorin (cytoprotectant for severe MTX toxicity & reduced folate replacement therapy) generates the folate cofactors needed to ensure the continued synthesis of pyrimidine and purine synthesis in healthy cells

• What is used along antifolates to reduce toxicity? 

Leucovorin

• Which are some of the examples of increasing half-life or water solubility in antimetabolites?

• Cytidine-based anticancer agents (Cytarabine & Gemcitabine) → undergo initial phosphorylation by deoxycytidine kinase to monophosphate, with subsequent phosphorylations catalyzed by pyrimidine monophosphate and diphosphate kinases

  • Gemcitabine > Cytarabine (half life). Presence of fluoro group 

• Cytarabine & Daunorubicin → nanoliposome formulation for prolonged half-life

• Fludarabine → marketed as monophosphate nucleotide to enhance water solubility

  • Think of Flu(I)d = water soluble 

• Administration of which classes of mitosis inhibitors cause hypersensitivity and why? 

• Taxanes 

• Paclitaxel has enhanced risk of hypersensitivity reactions because it is administered with Kolliphor EL

• What are the major problems with Taxanes? What are some alternative drugs to circumvent those? 

• Low water solubility

• Paclitaxel must be administered in a vehicle of 50% alcohol/50% polyoxyethylated caster oil (Cremophor EL) → risk of hypersensitivity reactions without H1 antagonists and dexamethasone tx

• High P-gp mediated cellular efflux of paclitaxel and docetaxel can result in drug resistance

• Overexpression of efflux pumps (cabazitaxel isn’t susceptible to efflux pump action, unlike paclitaxel or docetaxel)

• Alternatives:

  • Docetaxel → greater water solubility than paclitaxel due to presence of free C10-OH group and formulated with polysorbate 80 (tween) rather than Kolliphor EL

  • Cabazitaxel →lower affinity for P-gp (not susceptible to efflux pump action, unlike paclitaxel or docetaxel); also formulated with polysorbate 80 (but antihistamine/corticosteroid pretreatment is still recommended)

  • Epothilones (Epothilone B and Ixabepilone) → mimic critical tubulin-binding groups, enhanced water solubility & lack of P-gp affinity, higher antineoplastic potency, uses Kolliphor EL for solubilization like paclitaxel (need premedication)

• How is the resistance developed by these agents? 

• Tubulin mutations (Mt stability and/or drug binding)

• Microfilament alterations (altered interactions between Mt and Mf)

• Tubulin/Mt alterations (altered tubulin isotype expression, changes in MAPs)

• Anti-apoptotic and signaling factors

• Why is paclitaxel used with capecitabine? 

• Paclitaxel is used with capecitabine (fluorouracil prodrug) in anthracycline-resistance metastatic breast cancer (MBC) 

  • Paclitaxel UPregulates thymidine phosphorylase (one of capecitabine’s activating enzyme)

• Which one of the Vinca alkaloids has the longest half-life?

• Vincristine (vinca alkaloid)