5-Kearns- Cell Cycle Specific

What are the 2 classes of Topoisomerase Inhibitors and the names of the drugs in those classes?

• Camptothecins

  • Irinotecan (Camptosar)

  • Topotecan (Hycamtin)

• Epipodophyllotoxins

  • Etoposide

  • Teniposide

What phase of the cell cycle does each topoisomerase inhibitor class inhibit?

• Camptothecins- S PHASE

• Epipodophyllotoxins - S—>G2 TRANSITION

Which topoisomerases does each class of drugs inhibit? Top I or Top II?

• Camptothecins- Top I

• Epipodophyllotoxins- Top II

What is the MOA Camptothecins?

bind to DNA-top I complex

• intermolecular interactions between drug and top lead to a stable Drug-DNA-Top I complex

Camptothecins can have a lactone or hydroxy acid R group. Which is more active?

• lactone—> more active

• hydroxy acid—→ less active

Answer the following table about Topoisomerase inhibitors:

Generic	Brand	Class	Admin	ADRs
Irinotecan
Topotecan
Etoposide

Which top inhibitor is a prodrug? What is the active metabolite?

Irinotecan—> active metabolite is SN-38

What is a normal creatine clearance?

90 ml/min

Topotecan and Etoposide are __________ eliminated and dosed based on CrCl or kidney failure.

renally

Epipodophyllotoxins like Etoposide and Teniposide have a resistance to what?

P-gp

Camptothecins are isolated from a tree called Camptotheca acuminata and Epipodophyllotoxins are isolated from mandrake root. Can natural products containing these substances be useful in cancer?

nah

Do topoisomerase inhibitors work through covalent or intermolecular bonds?

intermolecular

Antimetabolites inhibit _______________ and are specific to what phase?

inhibit DNA synthesis and are S PHASE SPECIFIC

Do antimetabolites have a cytotoxic or cytostatic effect? What is the difference?

cytostatic effect!!!

• cytostatic- can reverse, keeps the DNA intact/locks it up and the cell cycle will not progress

• cytotoxic- CANNOT reverse, induces apoptosis and there is not return

Name the classes and drugs within the them that are considered “antimetabolites”

• antifolates

  • methotrexate

• pyrimidine antagonists

  • pemetrexed

  • 5-FU

  • capecitabine

• purine antagonists

  • 6-MP

  • 6-Thioguanine

• nucleoside analogues

  • cytrabine

  • gemcitabine

• miscellaneous:

  • pentostatin

  • hydroxyurea

Methotrexate inhibits what enzyme? What conversion does this block?

dihydrofolate reductase (DHFR)—> inhibits the conversion of dihydrofolate to tetrahydrofolate

Inhibiting folic acid would inhibit which of the following:

a. purine synthesis

b. pyrimidine synthesis

c. both

c (one exception is the pyrminidine cytosine)

Answer the following about methotrexate:

1. To exert its action methotrexate needs what to get into the cell?

2. How can methotrexate be administered?

3. What are the ADRs of methotrexate?

4. What drugs should be avoided?

1. transporters

2. IV, IM, SQ, intrathecal, oral

3. BMS, N/V/D. alopecia, mucositis, rash, hepatotoxicity, nephrotoxicity

4. drugs that decrease excretion (cisplatin, PCNs, sulfa, NSAIDs)

Once methotrexate enters a cell what happens to it?

becomes polyglutamated

What is the rescue drug for Methotrexate? When is it usually required?

• rescue drug- LEUCOVORIN (wellcovorin)

• required for high dose MTX

What drugs are pyrimidine antagonists? (brand/generic)

• Pemetrexed (Alimta)

• Fluorouracil (5-FU)

What is the MOA of Pemetrexed? What are these enzymes that this drug inhibits normally do?

1. weak inhibitor of DHFR

   • converts dihydrofolate to tetrahydrafolate

2. INHIBITS THYMIDYLATE SYNTHASE

   • thymidylate synthase normally converts dUMP to dTMP

3. INHIBITS glycinamide ribonucleotide formyltransferase (GARFT)

   • tetrahydrofolate to IMP

How does the MOA of methotrexate compare to pemetrexed?

methotrexate only inhibits 1 enzyme, while pemetrexed inhibits 3 enzymes

Answer the following about Pemetrexed (Alimta):

• administration

• what must be supplemented?

• avoid use in what?

• ADRs

• IV administration

• B12 and folic acid MUST be supplemented

• avoid use in decrease kidney function (and NSAIDS)

• ADRs:

  • myelosuppression

  • others: fatigue/drowsiness, renal toxicity, rash, N/V/D, stomatitis, pharyngitis

What is the MOA of 5-FU?

inhibitor of THYMIDYLATE SYNTHASE!!!!!

Which pyrimidine antagonist is a pro-drug? What is the active metabolite? Is the active metabolite hydrophilic or lipophilic?

• 5-FU IS A PRODRUG!!!!!!!!!!!!!!!!!!!!!

• active metabolite is Capecitabine

• VERY LIPOPHILLIC!! (good for solid tumors)

How is capecitabine (prodrug of 5-FU) metabolized?

the enzyme CYTIDINE DEAMINASE converts Capecitabine to 5-FU

If the enzyme cytidine deaminase was overexpressed, what would happen to the concentration of 5-FU in cells?

increase

What enzyme is responsible for the catabolism of 5-FU?

DPD (dihydropyrimidine dehydrogenase)

What drugs are purine antagonists?

• mercaptopurine (6-MP) (Purinethol)

What is the main goal of purine antagonists?

inhibit the synthesis of purines (A and G) by messing with IMP

What is the MOA of Purine antagonists?

Overall: Block conversion of IMP to GMP and AMP

1. HGPRT (Hypoxanthine guanine phosphoribosyl transferase) converts 6-MP into TIMP and TGMP

2. TIMP INHIBITS 3 pathways associated with IMP

   • the conversion of PRPP to IMP

   • conversion of IMP to AMP

   • conversion of IMP to XMP

3. TGMP is incorporated into DNA/RNA as false nucleotides

Purine antagonists are PRODRUGS that must be converted to what? using what enzyme?

must be converted to ribonucleotides (TIMP and TGMP) by hypoxanthine guanine phosphoribosyl transferase (HGPRT)

What is a prodrug for 6-MP?

Azathioprine

Answer the following Mercaptopurine (6-MP):

• administration?

• decrease dose if taken with…

• ADRs

• oral administration

• decrease dose with allopurinol (gout medication)

• ADRs- BMS, hepatotoxicity, hyperuricemia

  • others: rash, N/V/D, malaise

Which of the following are administered as an anti-cancer tx?

a. nucleoside analogues

b. nucleotide analogues

a

What are nucleoside analogues converted into? What is the result?

nucleoside analogues converted into nucleotide analogs for activity (phosphorylation). inhibits DNA elongation——results in apoptosis of the cell.

What drugs are nucleoside analogues? (brand/generic)

Cytarabine (ara-C) (Cytosar-U)

Vyxeos is a combination of cytarabine and _____________.

daunorubicin

Answer the following about Cytarabine:

• administration

• analogue of what?

• inhibits what?

• ADRs

• IV, intrathecal

• cytidine analogue (AraCTP competes with dCTP)

  • inhibits DNA polymerase

• ADRs

  • BMS, N/V/D, cerebellar toxicity, malaise, conjunctivitis

Hydroxyurea inhibits what enzyme?

ribonucleotide reductase

How is hydroxyurea (Droxia) administered and what are the ADRs?

• administered orally

• ADRs- BMS, N/V/D, CNS disturbances, dysuria, stomatitis, alopecia, hepatotoxicity

PRACTICE:

Which of the following are NOT cell cycle specific:

a. nucleoside analogues

b. alkylating agents

c. pyrimidine antagonists

d. purine antagonists

e. methotrexate

b (ALL OF THE ANTIMETABOLITES ARE S PHASE SPECIFIC!!!)

What classes of drugs inhibit microtubules? What are the drugs within each class?

• vinca alkaloids

  • Vinblastine

  • Vincristine

• taxanes

  • paclitaxel

  • docetaxel

Microtubule inhibitors are specific to what phase?

M phase

How do Vinca alkaloids and Taxanes inhibit microtubules? (polymerization, and stabilization)

• vinca alkaloids- INHIBIT POLYMERIZATION

  • microtubule DESTABILIZING (means we stop it from growing)

• taxanes- INHIBIT DEPOLYMERIZATION

  • microtubule STABILIZING (means as we grow we just keep it wherever it is)

How do vinca alkaloids cause microtubule destabilization? Does it bind at the + end or - end

binding to GTP binding sites on the + end, and inhibits GTP from coming in and the microtubule will not grow any more

What’s the difference in SAR between Vincristine and Vinblastine?

• Vincristine- more hydrophilic- has oxygen

  • cleared more slowly, cumulative toxicity

• Vinblastine- more lipophilic- has methyl

  • more potent, better in solid tumors

All microtubule inhibitors have a resistance to what?

P-gp

Vinca alkaloids should NEVER be administered how?

intrathecal

Answer the following about Vinca alkaloids:

Generic	Brand	Admin	t 1/2	CYP metabolizer	ADRs
Vincristine
Vinblastine

Can you administer a vinca alkaloid with a taxane?

yes—> give combo

Paclitaxel can be administered in what because of its low solubility?

castor oil (FYI: there’s also albumin formulations)

Answer the following about taxanes:

Generic	Brand	Admin	CYP metabolizer	ADRs
Paclitaxel
Docetaxel

In general all microtubule inhibitors (taxanes and vinca alkaloids) have a risk of what ADR?

peripheral neuropathy