Antineoplastic Agents Flashcards
Alkylating agents
MOA
Alkylating agents work by binding at the N7 position of guanine and form a crosslink in the DNA
Alkylating agents
General Side effects
- Alkylating agents affect all cells with rapid turnover (skin, BM, GI, reproductive system)
- BM depression (anemia, leukopenia, thrombocytopenia, etc)
- alopecia
- ulceration of mucosal surfaces
- potentially carinogenic/teratogenic
- permanent amenorrhea
What drugs are in the nitrogen mustard subclass of the alkylating agents?
Nitrogen mustards inlude
cyclosphophamide
ifosfamide
Melphalan
Mechlorethamine
Cyclosphosphamide
does it require activation?
what is the major side effect associated with cyclosphosphamide?
Cyclosphosphamide is a prodrug that requires metabolic activation by hepatic P450.
The active metabolites acrolein and phosphoramide mustard cause the cytotoxic effects.
Acrolein also destroyes the urothelium and causes hemorrhagic cystitis
Cyclophosphamide
clinical use as a chemotherapy agent
cyclophosphamide
non-Hodgkin’s lymphoma
Burkitt’s Lymphoma
CLL
neuroblastoma
Willms tumor
rhabdomyosarcoma
Ewing Sarcoma
How do we prevent Hemorrhagic cystitis?
what drug causes it?
Cyclophosphamide’s active metabolite Acroline causes hemorrhagic cystitis.
We can prevent hemorrhagic cystitis with:
adequate hydration, mesna (N-acetylcysteine)
Ifosfamide
MOA
Side effects
Clinical indications
Ifosfamide is an analog of cyclophosphamide with a similar MOA and side effect profile. It must be activated by P450.
Ifosfamide can cause CNS toxicity that can result in encephalopathy. Other side effects include Hemorrhagic cystitis and nephrotoxicity
Ifosfamide
Clinical use
Ifosfamide is used for the treatment of
germ cell testicular cancer and sarcomas
What drugs are in the Nitrosoureases sub group of Alkylating agents?
Nitrosoureas
- carmustine (BCNU)
- Lomustine (CCNU)
Nitrosoureas
MOA
Clinical indication
Carmustine and Lomustine alkylate DNA binding at the O6 position of guanine
- Clinical use:
- Brain tumors (glioblastoma multiforme)
- multiple myeloma, hodgkin and non-hodkin
Nitrosoureas
Side effects
Side effects of carmustine and lomustine include
N/V
BM depression
Pulmonary, renal and hepatic toxicity
Busulfan
MOA
Indications
Busulfan binds to the N7 of guanine.
CML (although most patients have the Philadelphia chromosome, t(9;22) which can be targeted with imatinib
Busulfan
Side effects
Busulfan
N/V
BM suppression
Pulmonary fibrosis
Adenal insufficiency
Skin hyperpigmentation
Nonclassic Alkylating Agents
procarbazine
decarbazine
Procarbazine: Nonclassic Alkylating Agents
MOA
procarbazine
inhibits DNA, RNA, and protein synthesis but the mechanism is unclear
Procarbazine
Side Effects
Procarbazine
CNS depression
highly carcinogenic, mutagenic, and teratogenic
Weak MAO inhibitor which can lead to a hypertensive crisis if given with other MAOi, TCA, or cheese and wine
Disulfiram-like reactions
Platinum analogs of alkylating agents include:
Platinum analogs
cisplatin
carboplatin
oxaliplatin
cisplatin
MOA
cisplatin
cross-links DNA at N7 of guanine
broad range of antitumor activity
Cisplatin
Side Effects
Cisplatin
Neurotoxicity
Ototoxicity
Nephrotoxicity (prevent with hydration, chloride diuresis, and amifostine)
what phase of the cell cycle do the alkylating agents target?
They are non-specific.
Antimetabolites target which phase in the cell cycle?
S phase
Methotrexate
MOA
Methotrexate competitively binds to and inhibits dihydrofolate reductase resulting in the inhibition of synthesis of tetrahydrofolate and inhibits dTMP and DNA synthesis
Methotrexate:
Clinical Use
- Chemotherapy:
- Multiple cancers: ALL, lymphomas, breast, head, neck, osteosarcoma, choriocarcinoma
- non-chemotherapy:
- GVHD
- psoriasis
- RA
Methotrexate:
Side Effects
Methotrexate
- BM depression (neutropenia and thrombocytopenia)
- Teratogen
- Alopecia, GI toxicity, dermatitis, pulmonary fibrosis
What drug is administered along with methotrexate to “rescue normal cells from toxicity?”
Leucovorin
its a reduced folate but its mechanism is unclear
What drugs are pyrimidine antagonists?
5-florouracil
cytarabine
gemcitabine
5-FU
MOA
5-FU is inactive and requires activation to FdUMP which will inhibit thymidylate synthase
Cytarabine
MOA
Cytarabine
cytidine analog and a prodrug that needs activation to Ara-CTP.
Ara-CTP competes with dCTP and inhibits DNA synthesis
S-phase specific
Cytarabine:
Clinical Use
Cytarabine use is limited to
hematological malignancies
Cytarabine
Side effects
Cytarabine
N/V
BM depression
cerebellar ataxia
Gemcitabine
MOA
Gemcitabine
inhibits ribonucleotide reductase which decreases dNTP.
Inhibits DNA polymerase
incorporates into DNA and leads to chain termination
What drugs are purine antagonists?
Purine antagonists:
6-Mercaptopurine
6-Thioguanine
Fluarabine
6-MP and 6-TG
MOA
6-MP and 6-TG
require activation by HGPRT and inhibit de novo purine nucleotide synthesis
6-MP and 6-TG
Clinical Use:
Side effects:
Drug-drug interactions
6-MP and 6-TG
AML and ALL (acute)
hepatotoxicity (1/3 of patients sho some cholestatic jaundice)
6-MP interacts with allopurinol or febuxostat
*6-MP is metabolized by xanthine oxidase. Allopurino and febuxostat are xanthine oxidase inhibitors so they will stop the metabolism (inactivation) of 6-MP
Fludarabine
MOA
Clinical Use
Side Effects
Fludarabine incorporates into DNA and inhibits ribonucleotide reductase. It is used for treatment in Non-Hodgkin’s lymphoma and CLL.
Immunosupression
Hydroxyurea
MOA
Hydroxyurea
inhibits ribonucleotide reductase resulting in a depletion of intracellular dNTPs leading to inhibition of DNA synthesis
Hydroxyurea
Clinical Use
Hydroxyurea
AML, CML, melanoma
Sickle Cell disease
