Alkylating agents, cell cycle non specific drugs Flashcards
cell cycle specific drugs are what?
schedule dependent!
-duration and timing of drug admin is more important than dose!!
slow growing tumors in Go (exited cell cycle)- are what?
-cell cycle non-specific drugs- dose-dependent!!!
Drugs that Alkylate DNA- 2 mech’s
- cross-link DNA
- insert a methyl or ethyl molecule into DNA
Triazenes- distinction, drugs
DNA alkylation- methylation!! -Dacarbazine -Procarbazine -Temozolomide (DPT)
Nitrosoureas- distinction, drugs
DNA alkylation/cross-linking; protein carbamylation
- Carmustine
- Lomustine
Dacarbazine- therapeutic use
-melanoma
Procarbazine- therapeutic use
-glioma
Temozolomide- therapeutic use
-glioma and astrocytoma
Carmustine and Lomustine- therapeutic use
brain tumors!
Streptozocin- therapeutic use?
- selective at islet B cells
- insulinomas!
Nitrogen Mustards- distinction, drugs
crosslinks DNA -Cyclophosphamide -Ifosfamide -Mechlorethamine (vesicant) (CIM)
Melphalan (nitrogen mustard)- distinction
-targeted to phenylalanine transporters
Chlorambucil (nitrogen mustard)- distinction
oral drug
Busulfan (nitrogen mustard)- distinction
alkyl sulfonate
Estramustine (nitrogen mustard)- distinction
Anti-androgen and alkylation
cross-linking agents are what?
cell cycle non-specific!!
- if cant repair- tumor dies- benefit!!
- if can repair- tumor lives- may have acquired new mutations- risk
selectivity and resistance to DNA alkylating/cross linking agents
- DNA repair capability
- multidrug resistance
Mechlorethamine- distinction
-instantaneous act by water upon infusion- vesicant!- can cause blisters!!!!!
Cyclophosphamide- moa
- act by liver
- Acrolein- urotoxic metabolite- in bladder
- Phosphoramide mustard- active metabolite- in tumor
Ifosfamide- moa
- act by liver
- Acrolein- urotoxic metabolic- in bladder
- isophosphoramide mustard- active metabolite- in tumor
- chloroacetaldehyde- neurotoxicity
used for hemorrhagic cystitis caused by Acrolein
MESNA!!
-SE- hypersensitivity rxn
Estramustine- specially used for?
castration-resistant prostate cancer! (anti-androgenic effects)
-however, inc risk of arterial and venous thromboembolic events
Nitrosoureas- dual actions
- DNA alkylation
- Protein modification
Nitrosoureas that penetrate CNS
-Carmustine (IV)
-Lomustine (po)
used for brain cancers!!
Triazenes- drugs
- Dacarbazine
- Procarbazine
- Temozolomide
Dacarbazine vs Temozolomide
- Dacarbazine- IV- doesnt penetrate CNS
- Temozolomide- PO- penetrates CNS!!- astrocytoma, glioblastoma
what influences the efficacy of Temozolomide?
- MGMT status- if low expression, DNA damage causes apoptosis- tumor is susceptible
- epigenetic silencing of MGMT- marker for efficacy
Cisplatin- related compounds
- Cisplatin- stable in plasma and high Cl- milieu
- Carboplatin
- Oxaloplatin
Cisplatin- therapeutic use, dose limiting toxicity
- testicular cancer (with bleomycin, vinblastine, or etoposide), ovarian cancer
- nephrotoxicity, ototoxicity (acoustic n damage)!!
Carboplatin- therapeutic use, dose limiting toxicity
- ovarian cancer
- neutropenia
Oxaloplatin- therapeutic use, dose limiting toxicity
- colorectal cancer
- neuropathy- cold induced!
Cisplatin- moa
-forms intra-strand crosslinks- poorly repaired
cisplatin- mech of resistance
- dec uptake or inc efflux
- glutathione (causes neutralization)
- inc DNA repair
- defective apoptosis
