Fitzpatrick - Anti-Neoplastic Drugs, Purine Antimetabolites Flashcards Preview

Hematology and Oncology > Fitzpatrick - Anti-Neoplastic Drugs, Purine Antimetabolites > Flashcards

Flashcards in Fitzpatrick - Anti-Neoplastic Drugs, Purine Antimetabolites Deck (33)
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1
Q

What is the main MOA for MTX?

A

Competitive inhibition of DHFR.

2
Q

How does MTX enter the tumor cell?

A

Through RFC, via energy dependent transport.

3
Q

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

A

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

4
Q

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

A

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

5
Q

Excretion of Intermediate/LDMTX v. HDMTX.

A
  • Int/LDMTX = 80-90% renal excretion.

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

6
Q

Dose Limiting Toxicities of MTX (two).

A
  1. GI toxicity - mucositis (oral and GI), SI ulcers/bleeding, Diarrhea
  2. Marrow suppression
7
Q

Toxicity: intrathecal injection of MTX

A

Neurotoxicity

8
Q

**Toxicity: HDMTX

A

**Renal toxicity due to 7-hydroxy-MTX

9
Q

MOA of premetrexed

A

Competitive inhibition of TS and GAR transformylase

10
Q

How is premetrexed MOA different than MTX’s effects?

A

It has negligible effect on DHFR.

11
Q

Malignant pleural mesothelioma, think what drug to tx?

A

Premetrexed

12
Q

Three enzymes that act on 6-Mercaptopurine.

A
  1. TPMT = ThioPurine MethylTransferase (liver, inactivation)
  2. XO = Xanthine Oxidase (liver, inactivation)
  3. HPRT = Hypoxanthine PhosphoRibosylTransferase (cells, activation )
13
Q

Action of Hypoxanthine PhosphoRyloxylTransferase

A

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

14
Q

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

A

Inosine MonoPhosphate DeHydrogenase and TPMT.

15
Q

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

A

TPMT

16
Q

What enzyme only activates 6-MP?

A

Hypoxanthine PhosphoRibosylTransferase

17
Q

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?

A

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

18
Q

Allopurinol and febuxostat are given for what condition?

A

Urate lowering via inhibition of XO.

19
Q

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?

A

6-MP, Azathrioprine, Theophylline

20
Q

Manage Tumor Lysis Syndrome with what two drugs? Why?

A

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

21
Q

Three results of tumor lysis syndrome.

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

= acute renal failure = worsened hyperK/PO3/Uricemia

22
Q
  • hypoK associated with …?

- hyperK associated with…?

A
  • hypoK=drug associated nephrotoxity

- hyperK = tumor lysis syndrome

23
Q

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

A

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

24
Q

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

A

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

25
Q

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

A
  • 6-MP, 6-TG

- Aggravate toxic myelosuppressive effects.

26
Q

Phenotypic genetic variants of TPMT gene.

A
  1. low/low = low TPMT activity
    2/ low/high = intermediate TPMT activity
  2. high/high = high TPMT activity
27
Q

Benefit with TPMT-H/H.

Risk with TPMT-H/H.

A

Benefit - Lower toxicity.

Risk - relapse.

28
Q

Benefit with TPMT-L/L.

Risk with TPMT-L/L.

A

Benefit - Efficacy.

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

29
Q

Fludarabine and cladribine are chemical analogs of what nucleotide?

A

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

30
Q

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

A

2 log kills

31
Q

**Cell Cycle Specific Drugs are dependent on…?

A

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

32
Q

Hrs in each phase of the cycle -

A
G0 = ?
G1 = 40-45% of time (6-12hrs)
S = 35-40% (6-8hrs)
G2 = 20% (3-4hrs)
M = 2% (1hr)
33
Q

Diagnostic threhold for detectable cancer - gompertzian model of tumor growth

A

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.