Chem IV: Anti-Metabolites

Question 1

How do anti-metabolites act as chemotherapy drugs?

In general, is this group of drugs cell cycle specific or non-specific?

Answer 1

Antimetabolites are structural analogs of naturally ocurring metabolites – they SUBSTITUTE for the naturally occurin gmetabolites in biochemical pathways and CAUSE CESATION of synthesis (usually nucleic acids).

Cell Cycle Specific during S-phase

Question 2

Methotrexate

What structural analog is methotrexate blocking?

What does methotrexate block the synthesis of?

How can a cell be rescued by MTX?

Answer 2

Methotrexate (MTX) is the structural analog of folic acid, differing only by the addition of a methyl group

MTX enters the cell via a specific folate carrier protein and MTX binds reversibly to DIHYDROFOLATE REDUCTASE (DHFR) –> dihydrofolate accumulates and decreasing TETRAHYDROFOLATE

tetrahydrofolate serves as a 1 carbon donor in PURINE synthesis, thus NA synthesis ceases

MTX and folic acid are polyglutamated by folypolyglutamate synthase –> polyglutamte forms are retained within cancer cells –> INC inhibitory effects on enzymes involved in purine and thymidylate synthesis

administration of tetrahydrofolate / leucovorin can rescue the cell from the cytotoxicity of MTX ONLY IF the MTX has NOT be polyglutamated (especially

Question 3

What is the limiting dose factor of methoterxate?

What are other AEs? (3)

When is dose reduction needed?

What are its uses? (6)

Forms of use available (3)

What is one thing to ensure while administrating?

Answer 3

Dose-limitation: Myelosuppression

AEs: N/V, stomatitis

Reduce in renal insufficience (metabolized in body and excreted in the urine)

For: lymphoma, leukemia, brain tumors, breast CA, RA, psoriasis

Intracathecal (esp for tumor cells in CSF/meningies), IV or oral

faint yellow color, so check when administrating into intrathecal space to ensure giving right drug! could be deadly if not.

Question 4

How does the following characteristic of MTX have an affect on its clinical impact:

Protein Bound

Answer 4

Highly prtein bound

If administerd with drugs which displace MTX from albumin, binding sites may potentiate toxicity

Careful w/: Aspirin, sulfonamides, penicillins

Question 5

How does the following characteristic of MTX have an affect on its clinical impact:

Volume of distribution is total body water

Answer 5

MTX can gain access to third psace and accumulation of fluid - will slowly leak out and cause a prolong tail of excretion.

Contraindicated in the context of ascities, edema and pleural effusions

Question 6

How does the following characteristic of MTX have an affect on its clinical impact:

MTX is filtered, secreted AND REABSORBED by the kidney:

Answer 6

Use with caution in patients with impaired renal function

DOSE REDUCTION for pts w/renal insufficiency

Question 7

How does the following characteristic of MTX have an affect on its clinical impact:

MTX is excreted by the kidneys as a SALT OF A WEAK ACID

Answer 7

Aspirin and penicillins also excreted this way by the kidney and can interfer with the urinary excretion of MTX

PROBENECID blocks the organic acid transprot system and will also interfere with excretion

Question 8

How does the following characteristic of MTX have an affect on its clinical impact:

MTX solubility markedly increases in alkaline pH

[solubility at pH=5 is 0.39 mg/ml; pH=6 is 1.55 mg/ml and pH=7 is 9.04]

Answer 8

Alkalinize exretion – INC solubiltity and thus promotes excretion!

[can give oral sodium bicar or IV to alkalinize urine]

T

Question 9

How does the following characteristic of MTX have an affect on its clinical impact:

Penetrates teh CNS when given in high doses

Answer 9

High IV doses may provide protection to CNS against spread of tumor!

Question 10

How do you administer high dose MTX with rescue? (6 steps)

Answer 10

High = 3-8 GRAMS

1. Hydration and alkalization of the urine using saline and bicarbonte IV
2. Check urine pH each void; continue administering sodium bar until pH reaches at least 7
3. When urine pH has reached at least 7, administer MTX
4. Begin IV or oral leucovorin rescue
5. Monitor MTX levels
6. STOP rescue when metotrexate level is

< 5 X 10^-7 M at 48 hours

Bone marrow and GI epithelium do not form polyglutamates, therefore able to be rescued

Question 11

Premetrexed:

MOA

Dose limiting factor? How could this be decreased

AEs (4)

Useful for: (2)

Answer 11

Premetrexed is in the MTX family

It is an ANTIFOLATE, since it disrupts folate dependent metabolic precesses; it is also transported into the cell via a flate carreier and polyglutamated – inhibits thymidylate synthesis

Dose-limitation: Myelosuppresion

pt can be pre-treated with VITAMIN B12 and ORAL FOLIC ACID to decrease the exten of myelosuppresion

AEs: Rash, stomatitis, diarrhea, hand foot syndrome

Useful for: lung cancer mesotheliom (w/cisplatin)

Question 12

Cytarabine / cytosine arabinoside:

MOA

How is its cytotoxicity measured?

Answer 12

Cell cycle specific during the S-phase

A pyramidine analog (taken up the cell via carreir mediated nucleoside transprot mxn) that undergoes suquential phosphorylation via kinase to the triphosphate –> ARA-CTP triphophate is incorporated into the DNA –> inhibits DNA polymerase/template function and chain elongation

Cytosine arabinoside has a schedule dependent cytotoxicity!

Therefore, how you give the drug determines cell kill; has greater cell kill if you give continuously because it has a very short half life and very narrow window (during S-phase) to interfer with cell DNA syntehsis and kill cell

The cytotoxicity is related to the duration of exposure of the cell to Ara-C; the retention of Ara-CTP at 4 hours is predictive of CA cell kill

Question 13

What is cytosine arabinoside used for?

What is the regimen usually given:

Answer 13

Used for treatment of leukemia; almost exclusively used for AML

Since it displays schedule dependent cytotoxicity, it is given:

3+7 regimen for AML

3 days of IV admin of anthracycline (doxy or dona)

7 days of continuous infusion of cytosine arabinoside (168 hrs)

*continuous is key*

High dose (2-3 grams) keeps drug around longer

Also approved for intrathecal administration

Question 14

What are the side effects of Cytosine Arabinoside (5)

how does this differ with high dose administration?

What is the dose limitation?

What is it metabolized by?

What is its half life?

Answer 14

SE: N/V, hair loss, hepatic tox, stomatitis

High dose also has cerebellar toxicity and conjunctivitis (give steroids to prevent chemoconjunctivitis)

Dose-limitaiton: myelosuppression

Metabolized by ubiquitous deaminase

Half-life: initial half-life is 7-20 minutes and the terminal half-life is 2 hours

recall it is S-phase specific + short half life –> schedule depedent cytotoxicity

Question 15

What other compound is in the same class with cytosine arabinoside?

What is this useful for?

Answer 15

Gemcitabine is also in the same class as cytosine arabinoside

MOA is similar to cytosine arabinoside

Myelosuppression is its dose limitation - MAJOR ISSUE!

Useful for: palliative tx of CA of pancreas and lung CA

Question 16

Fluorinated pyrimidine / 5-Fluorouracil:

MOA?

How does this drug differ from the other anti-metabolites?

Answer 16

5-FU needs to be bioactivated!!

MOA:

1. Production of FdUMP (via thymidine phosphorylase) which inhibits thymidylate synthetase- tetrahydrofolate + FdUMP binds tightly to thymidylate synthase and decreases the production of thymine nucletodies (thymine nucleotides –> thymineless death)
2. Sequential phosphorylation and incorporation into the RNA and DNA

Question 17

5-FU

SE: (12)

Answer 17

N/V, stomatitis, rash, diarrhea and myelosuppresion

HYPERPIGMENTATION of skin of the palms of the hands

INC sensitivity to sunlight

coronary artery vasospasms – angina! (rare; think of treating if 5-FU could be curative!)

Cerebellar toxicity

Excessive lacrimation

Hand-foot syndrome

Question 18

what is the role of leucovorin in the treatmetn with 5-FU?

Answer 18

Leucovorin ENHANCES the cytotoxicity of 5-FU!

5-dUMP + Leucovorin forms a strong inhibitory complex with thymidylate synthesis –> thymineless death

response rates higher with co-administered with leucovorin

Also enhances GI toxicity

NOTE: leucovorin enhances the cytotoxicty of 5-FU while it diminishes the toxicity/cytotoxicity of methotrexate

Question 19

What is a potential toxicity seen in pt taking 5-FU, related with an autosomal recessive disorder?

Answer 19

Initial enzyme used is dihydropyrimidine dehydrogenase (DPD)

DPD is invovled in the metabolism of uracil and thymine

YET! There is an AR disorder, in which the pt is deficient of DHD –> ends up with lifethreatening toxicity, GI disturbances (diarrhea), skin defects, stomatitis and severe myelosuppression

WITH NO threapeutic advantage

Question 20

What are the uses of 5-FU? (5)

How is it administered?

Answer 20

Used for: breast, head and neck, GI malignancies, and also frequently given cocomitantly with radiation therapy = radiation sensitizer (increases kill!)

There are different schedules of administration, and the toxicity profiles differ depending on the schedule of administration

Question 21

What is the oral form of 5-FU?

How does the MOA differ?

Answer 21

Capecitabine

Inside the cell, capecitabine is cleaved via thyamine phosphorylase into 5-FU –> same MOA

Question 22

how does the schedule of capecitabine differ from 5-FU?

How do the toxicities differ?

Answer 22

Cpecitabine is given 1250 mg/M^2 PO Q 12 hours for 14 days, every 21 days

AEs: rash, diarrhea, stomatitis, hand-foot syndrome, some myelosuppression (relative non-toxic though)

Can be subsituted for IV infusions of 5-FU

Question 23

What anti-metabolites have hand-foot syndrome as a side effect? (3)

What is hand-foot syndrome?

Answer 23

Capecitabine, 5-FU, pemetrexed

= usually seen at palms of hands and soles of feet, desquamation of the skin

Respond typically to stopping the drug, then ok to restart with dose reduction

Question 24

6-Mercaptopurine:

MOA:

Answer 24

Requires activation via hypoxanthine-guanine phophoribosyl transferease to form 6-thioinosinic acid –> inhibits enzymes needed for purine nucelotisde synthesis (de novo synth)

–> metabolized to INACTIVE 6-thiouric acid by xanthine oxidase (which is itself inhibited by allopurinol)

Question 25

When is it appropriate to reduce the dose of 6-mercaptopurine?

Answer 25

Dose reduction by 50-75% when co-administered with allopurinol

high killing –> thus high uric acid levels= might want to administer along with allopurinol to prevent gouty attack

Question 26

What is the dose limitation of 6-mercaptopurine?

What is it used for?

What are other drugs in this class? what is a big difference between the two?

Answer 26

Myelosuppresion is dose limiting

Used to treat childhood leukemia

Other drugs: 6-thioguanine (can be used at full dose even with allopurino is being used because 6-thio undergoes deanimation that does not involved the enzyme xanthine oxidase!)