Antineoplastic Agents

Question 1

Alkylating agents

MOA

Answer 1

Alkylating agents work by binding at the N7 position of guanine and form a crosslink in the DNA

Question 2

Alkylating agents

General Side effects

Answer 2

1. Alkylating agents affect all cells with rapid turnover (skin, BM, GI, reproductive system)
   
   1. BM depression (anemia, leukopenia, thrombocytopenia, etc)
   2. alopecia
   3. ulceration of mucosal surfaces
   4. potentially carinogenic/teratogenic
   5. permanent amenorrhea

Question 3

What drugs are in the nitrogen mustard subclass of the alkylating agents?

Answer 3

Nitrogen mustards inlude

cyclosphophamide

ifosfamide

Melphalan

Mechlorethamine

Question 4

Cyclosphosphamide

does it require activation?

what is the major side effect associated with cyclosphosphamide?

Answer 4

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

Question 5

Cyclophosphamide

clinical use as a chemotherapy agent

Answer 5

cyclophosphamide

non-Hodgkin’s lymphoma

Burkitt’s Lymphoma

CLL

neuroblastoma

Willms tumor

rhabdomyosarcoma

Ewing Sarcoma

Question 6

How do we prevent Hemorrhagic cystitis?

what drug causes it?

Answer 6

Cyclophosphamide’s active metabolite Acroline causes hemorrhagic cystitis.

We can prevent hemorrhagic cystitis with:

adequate hydration, mesna (N-acetylcysteine)

Question 7

Ifosfamide

MOA

Side effects

Clinical indications

Answer 7

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

Question 8

Ifosfamide

Clinical use

Answer 8

Ifosfamide is used for the treatment of

germ cell testicular cancer and sarcomas

Question 9

What drugs are in the Nitrosoureases sub group of Alkylating agents?

Answer 9

Nitrosoureas

1. carmustine (BCNU)
2. Lomustine (CCNU)

Question 10

Nitrosoureas

MOA

Clinical indication

Answer 10

Carmustine and Lomustine alkylate DNA binding at the O6 position of guanine

1. Clinical use:
   
   1. Brain tumors (glioblastoma multiforme)
   2. multiple myeloma, hodgkin and non-hodkin

Question 11

Nitrosoureas

Side effects

Answer 11

Side effects of carmustine and lomustine include

N/V

BM depression

Pulmonary, renal and hepatic toxicity

Question 12

Busulfan

MOA

Indications

Answer 12

Busulfan binds to the N7 of guanine.

CML (although most patients have the Philadelphia chromosome, t(9;22) which can be targeted with imatinib

Question 13

Busulfan

Side effects

Answer 13

Busulfan

N/V

BM suppression

Pulmonary fibrosis

Adenal insufficiency

Skin hyperpigmentation

Question 14

Nonclassic Alkylating Agents

Answer 14

procarbazine

decarbazine

Question 15

Procarbazine: Nonclassic Alkylating Agents

MOA

Answer 15

procarbazine

inhibits DNA, RNA, and protein synthesis but the mechanism is unclear

Question 16

Procarbazine

Side Effects

Answer 16

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

Question 17

Platinum analogs of alkylating agents include:

Answer 17

Platinum analogs

cisplatin

carboplatin

oxaliplatin

Question 18

cisplatin

MOA

Answer 18

cisplatin

cross-links DNA at N7 of guanine

broad range of antitumor activity

Question 19

Cisplatin

Side Effects

Answer 19

Cisplatin

Neurotoxicity

Ototoxicity

Nephrotoxicity (prevent with hydration, chloride diuresis, and amifostine)

Question 20

what phase of the cell cycle do the alkylating agents target?

Answer 20

They are non-specific.

Question 21

Antimetabolites target which phase in the cell cycle?

Answer 21

S phase

Question 22

Methotrexate

MOA

Answer 22

Methotrexate competitively binds to and inhibits dihydrofolate reductase resulting in the inhibition of synthesis of tetrahydrofolate and inhibits dTMP and DNA synthesis

Question 23

Methotrexate:

Clinical Use

Answer 23

1. Chemotherapy:
   
   1. Multiple cancers: ALL, lymphomas, breast, head, neck, osteosarcoma, choriocarcinoma
2. non-chemotherapy:
   
   1. GVHD
   2. psoriasis
   3. RA

Question 24

Methotrexate:

Side Effects

Answer 24

Methotrexate

1. BM depression (neutropenia and thrombocytopenia)
2. Teratogen
3. Alopecia, GI toxicity, dermatitis, pulmonary fibrosis

Question 25

What drug is administered along with methotrexate to "rescue normal cells from toxicity?"

Answer 25

Leucovorin its a reduced folate but its mechanism is unclear

Question 26

What drugs are pyrimidine antagonists?

Answer 26

5-florouracil cytarabine gemcitabine

Question 27

5-FU MOA

Answer 27

5-FU is inactive and requires activation to FdUMP which will i**nhibit thymidylate synthase**

Question 28

Cytarabine MOA

Answer 28

Cytarabine cytidine analog and a prodrug that needs activation to Ara-CTP. Ara-CTP competes with dCTP and inhibits DNA synthesis S-phase specific

Question 29

Cytarabine: Clinical Use

Answer 29

Cytarabine use is limited to ## Footnote **hematological malignancies**

Question 30

Cytarabine Side effects

Answer 30

Cytarabine N/V BM depression **cerebellar ataxia**

Question 31

Gemcitabine MOA

Answer 31

Gemcitabine inhibits ribonucleotide reductase which decreases dNTP. Inhibits DNA polymerase incorporates into DNA and leads to chain termination

Question 32

What drugs are purine antagonists?

Answer 32

Purine antagonists: 6-Mercaptopurine 6-Thioguanine Fluarabine

Question 33

6-MP and 6-TG MOA

Answer 33

6-MP and 6-TG require activation by HGPRT and inhibit de novo purine nucleotide synthesis

Question 34

6-MP and 6-TG Clinical Use: Side effects: Drug-drug interactions

Answer 34

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

Question 35

Fludarabine MOA Clinical Use Side Effects

Answer 35

Fludarabine incorporates into DNA and inhibits **ribonucleotide reductase**. It is used for treatment in **Non-Hodgkin's lymphoma and CLL**. **Immunosupression**

Question 36

Hydroxyurea MOA

Answer 36

Hydroxyurea inhibits ribonucleotide reductase resulting in a depletion of intracellular dNTPs leading to inhibition of DNA synthesis

Question 37

Hydroxyurea Clinical Use

Answer 37

Hydroxyurea AML, CML, melanoma Sickle Cell disease