Fitzpatrick - Anti-Neoplastic Drugs, Purine Antimetabolites

Question 1

What is the main MOA for MTX?

Answer 1

Competitive inhibition of DHFR.

Question 2

How does MTX enter the tumor cell?

Answer 2

Through RFC, via energy dependent transport.

Question 3

What does MTX accumulate in the cell as, and what does this molecule do?

Answer 3

Accumulates as MTX(Glu)n; which then inhibits DHFR, AICAR transformylase, and GAR transformylase.

Question 4

Inhibition of DHFR by MTX(Glu)n causes accumulation of what molecule?

Answer 4

DHF –> DHF(glu)n inhibits TS and AICAR.

Question 5

Excretion of Intermediate/LDMTX v. HDMTX.

Answer 5

• Int/LDMTX = 80-90% renal excretion.

- HDMTX = heaptic metabolism = 7-hydroxy-MTX (inactive, less soluble) = CRYSTALLURIA TUBULAR OBSTRUCTION

Question 6

Dose Limiting Toxicities of MTX (two).

Answer 6

1. GI toxicity - mucositis (oral and GI), SI ulcers/bleeding, Diarrhea
2. Marrow suppression

Question 7

Toxicity: intrathecal injection of MTX

Answer 7

Neurotoxicity

Question 8

**Toxicity: HDMTX

Answer 8

**Renal toxicity due to 7-hydroxy-MTX

Question 9

MOA of premetrexed

Answer 9

Competitive inhibition of TS and GAR transformylase

Question 10

How is premetrexed MOA different than MTX’s effects?

Answer 10

It has negligible effect on DHFR.

Question 11

Malignant pleural mesothelioma, think what drug to tx?

Answer 11

Premetrexed

Question 12

Three enzymes that act on 6-Mercaptopurine.

Answer 12

1. TPMT = ThioPurine MethylTransferase (liver, inactivation)
2. XO = Xanthine Oxidase (liver, inactivation)
3. HPRT = Hypoxanthine PhosphoRibosylTransferase (cells, activation )

Question 13

Action of Hypoxanthine PhosphoRyloxylTransferase

Answer 13

In cells, activates 6-MP to TIMP. TIMP then converted into active anti-neoplastic metabolites (TXMP and 6-methyl TIMP)

Question 14

How is TIMP converted into an active anti-neoplastic metabolite in tumor cells?

Answer 14

Inosine MonoPhosphate DeHydrogenase and TPMT.

Question 15

What enzyme is involved in both activation and inactivation of 6-MP?

Answer 15

TPMT

Question 16

What enzyme only activates 6-MP?

Answer 16

Hypoxanthine PhosphoRibosylTransferase

Question 17

A person begins 6-MP regimen. What two drugs interact with 6-MP that result in risk of excess exposure to 6-MP/require dosage adjustments?

Answer 17

Allopurinol and febuxostat - both inhibit XO, which accounts for 80% of 6-MP metabolism.

Question 18

Allopurinol and febuxostat are given for what condition?

Answer 18

Urate lowering via inhibition of XO.

Question 19

A person has gout and needs to take either allopurinol or febuxostat. Metabolization of what three drugs (chemo, immunosuppressant, asthma) by XO would be disrupted if allopurinol or Febuxostat were started for gout tx?

Answer 19

6-MP, Azathrioprine, Theophylline

Question 20

Manage Tumor Lysis Syndrome with what two drugs? Why?

Answer 20

Allopurinol (inhibits XO to prevent nephrotoxicity resulting from uric acid excess) + 6-MP (LOWER DOSE bc inactivated by XO)

Question 21

Three results of tumor lysis syndrome.

Answer 21

1. K+ release = HYPERKALEMIA
2. Nucelotide release = HYPERPHOSPHATEMIA and hypocalcemia
3. Purine release = HYPERURICEMIA

= acute renal failure = worsened hyperK/PO3/Uricemia

Question 22

• hypoK associated with …?

- hyperK associated with…?

Answer 22

• hypoK=drug associated nephrotoxity

- hyperK = tumor lysis syndrome

Question 23

Tumor Lysis Syndrome management with ___ for hyperuricemia associated with malignancy.

Answer 23

Pegloticase (UA-oxidase), IV dosing Q 2-weeks.

Question 24

What purine antimetabolite has no drug interaction with XO inhibitors (allopurinol or febuxostat)?

Answer 24

6-thiogianine; bypasses the XO inactivation step (only metab by TPMT and activated by HPRT)

Question 25

Allelic variation on TPMT can modulate clearance of what two drugs? And drugs that inhibit TPMT may aggravate what?

Answer 25

• 6-MP, 6-TG

- Aggravate toxic myelosuppressive effects.

Question 26

Phenotypic genetic variants of TPMT gene.

Answer 26

1. low/low = low TPMT activity
   2/ low/high = intermediate TPMT activity
2. high/high = high TPMT activity

Question 27

Benefit with TPMT-H/H.

Risk with TPMT-H/H.

Answer 27

Benefit - Lower toxicity.

Risk - relapse.

Question 28

Benefit with TPMT-L/L.

Risk with TPMT-L/L.

Answer 28

Benefit - Efficacy.

Risk - Myelosuppression and Secondary malignancy (dt mutations in protoncogenes or tumor suppressors)

Question 29

Fludarabine and cladribine are chemical analogs of what nucleotide?

Answer 29

Adenosine - 2’ position of sugar and 2 position of adenosine.

Question 30

Kill logs to: 1)shrink tumor prior to surgical removal (neoadjuvant) and 2) give after tumor removal to prevent reoccurence (adjuvant)

Answer 30

2 log kills

Question 31

**Cell Cycle Specific Drugs are dependent on…?

Answer 31

**Schedule dependent - Duration/timing affect efficacy more than the dose.

Question 32

Hrs in each phase of the cycle -

Answer 32

G0 = ?
G1 = 40-45% of time (6-12hrs)
S = 35-40% (6-8hrs)
G2 = 20% (3-4hrs)
M = 2% (1hr)

Question 33

Diagnostic threhold for detectable cancer - gompertzian model of tumor growth

Answer 33

10^9 cells

1. Initial tumor growth = first order/exponential
2. Once detectable, small tumor grows slower, but still high growth fraction.
3. Detectable cancer (10^9) has a slow growth rate/low growth fraction.