Topoisomerase Inhibitors

Question 1

What does topoisomerase do?

Answer 1

Cuts DNA strands to relieve tension and allow the strand to unwind.

Question 2

What do topoisomerase inhibitors do?

Answer 2

Bind to the toperisomerase after it has cut the strand once to prevent the strand from unwinding, decreasing DNA synthesis. Kills rapidly dividing cells.

Question 3

What are irinotecan and topotecan?

Answer 3

Toperisomerase I inhibitors; camptothecin analogs

Question 4

What is the brand name of irinotecan?

Answer 4

Camptosar, CPT-11

Question 5

What is the brand name of topotecan?

Answer 5

Hycamtin

Question 6

What is the active metabolite of irinotecan?

Answer 6

SN-38

Question 7

What formulation is irinotecan available in now?

Answer 7

Liposomal

Question 8

What formulations is topotecan available in?

Answer 8

IV and PO

Question 9

What are the toxicities of irinotecan?

Answer 9

Early diarrhea, late diarrhea, and hallmark toxicities

Question 10

When does irinotecan’s early diarrhea occur?

Answer 10

During infusion

Question 11

What are the characteristics of irinotecan’s early diarrhea?

Answer 11

Cholinergic storm (SLUD - salivation, lacrimation, urination, defecation)

Question 12

What is used to treat the cholinergic storm of irinotecan’s early diarrhea?

Answer 12

Atropine (anti-cholinergic) - 0.25 mg to 1 mg IV. If cholinergic storm occurs once, patient must receive prophylactic treatment of atropine before every irinotecan dose.

Question 13

When does irinotecan’s late diarrhea occur?

Answer 13

~12 to 24 hours after the infusion

Question 14

What is used to treat irinotecan’s late diarrhea?

Answer 14

Loperamide 4 mg initially, then 2 mg Q2H until no loose stools for 12 hours

Question 15

True or false. A patient may exceed the OTC of loperamide when treating irinotecan’s late diarrhea.

Answer 15

True. May exceed OTC max dose of 16 mg/day, but not for longer than 48 hours without medical supervision

Question 16

What are some of the hallmark toxicities seen in irinotecan?

Answer 16

Myelosuppression, diarrhea, a little nausea, a little mucositis

Question 17

What converts irinotecan to SN-38?

Answer 17

Carboxylesterase

Question 18

What converts irinotecan to its two inactive metabolites?

Answer 18

CYP 3A4

Question 19

What converts irinotecan’s two inactive metabolites to SN-38?

Answer 19

Carboxylesterase

Question 20

What makes SN-38 inactive (SN-38G)?

Answer 20

UGT 1A1 (glucoronidase enzyme)

Question 21

Where is beta glucoronidase produced?

Answer 21

The intestines

Question 22

What does beta glucoronidase do?

Answer 22

Converts SN-38G back to SN-38 (reabsorbs). Can cause more myelosuppression

Question 23

How are SN-38 and SN-38G eliminated?

Answer 23

Fecally

Question 24

How can elevated bilirubin affect irinotecan pharmacokinetically?

Answer 24

Greater toxicity. Seen in hepatic dysfunction and Gilbert’s syndrome

Question 25

How does smoking affect irinotecan pharmacokinetically?

Answer 25

Induces the effect of UGT 1A1, leading to decreased toxicity (better tolerated) /effect (UGT inducer)

Question 26

What drugs are UGT inducers?

Answer 26

Carbamazepine, phenobarbital, and phenytoin. Have to give these patients a significantly higher dose or you will be under-dosing them by almost a factor of 2.5.

Question 27

What does it mean if a patient is UGT 1A1*28 deficient?

Answer 27

More susceptible to irinotecan toxicities, diarrhea, and myelosuppression. Need a 20-25% dose reduction

Question 28

What education is important for patients with diarrhea while on irinotecan?

Answer 28

Importance of staying hydrated

Question 29

How can you remember that irinotecan is a toperisomerase I inhibitor?

Answer 29

Irinotecan begins with the Roman numeral I

Question 30

What does toperisomerase II do?

Answer 30

Ligates two strands of DNA and results in re-ligation afterwards. Cuts two strands, unwinds, and re-ligates.

Question 31

How do toperisomerase II inhibitors work?

Answer 31

Poison the toperisomerase II effect. Allows the strands to be cut and unwound, but prevents re-ligation from happening. Leads to S phase G2 cell cycle arrest of that interface, because inhibiting DNA synthesis. Rapidly dividing cells are more susceptible to toperisomerase II inhibition.

Question 32

What are epipodophyllotoxins?

Answer 32

Toperisomerase II inhibitors derived from the natural toxins of the American Mayapple

Question 33

What are two examples of epipodophyllotoxins?

Answer 33

Etoposide and teniposide

Question 34

What is etoposide’s brand name?

Answer 34

Toposar, VP-16

Question 35

What is etoposide phosphate’s brand name?

Answer 35

Topophos

Question 36

How is etoposide phosphate different from etoposide?

Answer 36

• Increased solubility. Etoposide is lipophilic. The phosphate has alcohol in it to allow for better solubility.
• Allows for faster infusion. Etoposide alone, if given too fast, can cause hypotension because of its lipophilicity (hypotension is rate limiting)
• Still not used as commonly as etoposide because of its cost

Question 37

What formulations is etoposide available in?

Answer 37

IV and PO.

Question 38

What is the IV rate of administration for etoposide?

Answer 38

Usually 30-60 minutes. Rate limited by hypotension

Question 39

What is the unique toxicity of etoposide and what causes it?

Answer 39

Secondary leukemia. Because DNA is left open and base pairs are exposed, more risk for mutations. Most often, the signature mutations seen are 11q23 (MLL gene) mutations.