Anti-Tumor Pharmacology

Question 1

What type of cancer has been most difficult to treat in the US?

Answer 1

Lung cancer

Question 2

Why is chemotherapy needed on top of surgery?

Answer 2

Drugs need to seek out and eradicate tumors at metastatic sites away from the primary tumor foci, which are undetected

Question 3

What type of tumor is most difficult to treat and why?

Answer 3

A slow-growing tumor

1. These tumors do not replicate DNA very often (maybe once every 80 days) and our S-phase drugs will not be as effective against them
2. Many cells become drug resistant
3. Many can repair damage (i.e. anti-alkylation)

Question 4

What cell types are typically adversely affected in chemotherapy regimens for rapidly-growing tumors?

Answer 4

Rapidly dividing cells in the human:

i.e. GI tract, bone marrow

Question 5

What doubling time is considered medium vs fast which dictates response? Give example tumors

Answer 5

<30 days doubling = fast, drug responsive (high growth fraction)
i.e. leukemias, lymphomas

40-60 day doubling = medium, some drug response
i.e. sarcomas

Question 6

What are examples of slow-growing tumors?

Answer 6

Lung, breast, colon

> 80 day doubling, 5% growth fraction

Question 7

What is needed for a tumor to grow as it grows larger?

Answer 7

Angiogenesis

Question 8

What phase of the cell cycle accounts for the long cell cycle time of tumors?

Answer 8

G0 phase (part of G1) - can be 0 to 80 days in fast vs slow growing tumors

Question 9

Traditionally, how has the dosage of a chemotherapy drug been determined?

Answer 9

Give near-maximum tolerated levels

Question 10

What drives the selective toxicity of alkylating agents?

Answer 10

They damage DNA in all cells (not just replicating cells), but cancer cells are less likely to undergo efficient repair of drug-induced damage to DNA

Question 11

For slow-growing tumors with few cells usually in the S phase: why is it so difficult to give S-phase drugs which kill them?

Answer 11

It is hard to keep the plasma concentration high enough for a long enough period of time to actually hit all of them without causing lethal host toxicity of normal cells

Question 12

What is the most difficult place in the body to reach once the tumor has metastasized?

Answer 12

the CNS

Question 13

How are non-cycle specific drugs given?

Answer 13

I.e. alkylating agents or antibiotics

Given with spacing between their doses which allows normal cells to recover from DNA damage

Question 14

What is a “self-limiting” drug? Example vs non-example

Answer 14

Cells which are S-phase inhibitors but also function to slow the cell through the other cell cycles -> stop cells from reaching S phase which they are toxic

Example: Methotrexate.

Non-example = purely S-phase drugs like cytosine arabinose and hydroxyurea

Question 15

List the anti-metabolites. Which one does not need to be phosphorylated?

Answer 15

1. Methotrexate - does not require phosphorylation
2. 5-Fluorouracil
3. 6-Mercaptopurine
4. Cytosine arabinose

Question 16

How does methotrexate work?

Answer 16

Inhibits dihydrofolate reductase by very tight binding, preventing regeneration of tetrahydrofolate and subsequent failure of thymidine synthesis

Question 17

What is the most common mechanism of methotrexate resistance?

Answer 17

Decreased cellular uptake of it
-> requires active transport into the cell to be effective. Relatively poorly absorbed and uptaken otherwise, just has a very tight binding if it actually gets into the cell

Question 18

What is the antidote to methotrexate and why isn’t it that effective?

Answer 18

Treatment with excess folic acid to save GI cells + bone marrow

Not that effective because not all of methotrexate’s toxicity comes from depletion of folate pool

Question 19

How is MTX excreted and why does this matter?

Answer 19

Excreted in urine - decrease dose in patients with impaired kidney function

Question 20

When 5-fluorouracil is given, what is the product which actually interferes with thymidine synthesis? Why is this relevant?

Answer 20

5-FU is made into 5-FU-deoxyribosephosphate (5UdRP) and sits in the active site of thymidylate synthetase along with reduced folate.

If MTX is given along with 5-FU, it can actually inhibit 5-FU’s action by limiting reduced folate’s availability

Question 21

How does 5-FU resistance develop?

Answer 21

Inhibition of enzymes making it into FUdRP (part of salvage pathway), or increased degradation of FU

Question 22

What does high vs low-dose FU do in terms of toxicity? Where is it inactivated?

Answer 22

High dose: depresses marrow and GI tract

Low dose: more effective - simply pain and swelling of palms and soles of feet “hand foot syndrome”

Inactivated in liver with high variance - give IV

Question 23

What is FU used to treat? Why?

Answer 23

Treats solid tumors with long-term low dosages, since leukemias often lack the salvage pathways required to activate it

Question 24

What is the mechanism of action of cytosine arabinose?

Answer 24

It is a cytosine nucleoside with the OH in the opposite direction

-> Phosphorylated 3 times, inhibits incorporation of deoxycytidine into DNA

Question 25

What does Ara-C effectively treat and its high dose toxicity?

Answer 25

Ara-C - effectively treats acute leukemias as it is not self-limiting High dose - irreversible CNS damage Typical: GI tract / marrow suppression

Question 26

What is 6-Mercaptopurine (6-MP) used to treat?

Answer 26

Acute leukemias Requires phosphorylation like Ara-C and is a guanine analog

Question 27

Why is allopurinol usually given in chemotherapy and how is it toxic?

Answer 27

Given since breakdown of nucleic acids due to many dying cells is required. Inhibition of xanthine oxidase will prevent gout. However, when given with 6-MP, can cause accumulation of 6-MP as well which is toxic to GI / marrow.

Question 28

What is the most lethal effect of alkylating agents?

Answer 28

The cross-linking of DNA

Question 29

What is cyclophosphamide a derivative of, and how does it actually work? How is it administered?

Answer 29

Nitrogen mustard Works by liver activation into alkylating products, which can be used to induce immune suppression as a broad spectrum agent Can be given orally

Question 30

What tumors does cyclophosphamide (CTX) treat?

Answer 30

Breast and ovarian tumors, also some slower growing lymphomas and Hodgkin's disease

Question 31

What is the primary unexpected adverse effect of CTX and how is this reversed?

Answer 31

Hemorrhagic cystitis / bladder cancer Reversed via administration of MESNA which can neutralize the metabolites in bladder

Question 32

What is the mechanism of action of temolozolomide? Its use?

Answer 32

Agent which has a breakdown product alkylating guanine residues (most common site for alkylating agents) Used for brain tumors

Question 33

What is the mechanism of action of cis-platinum and its use?

Answer 33

Crosslinks DNA Used against solid tumors like testicular / ovarian cancer

Question 34

What is the major toxicity of cis-platinum and how is this combated?

Answer 34

Major toxicity: Hearing loss (gong earings) and renal tubule damage (kidney-shaped purse) Also marrow toxicity - think of bone jewelry case Hydration + diuretics to prevent kidney damage

Question 35

What is the most likely defense mechanism against alkylating agents?

Answer 35

Enhanced DNA repair after alkylation

Question 36

What is the most common mechanism of drug resistance to natural products like antibiotics?

Answer 36

Multi-drug resistance transporter (MDR)

Question 37

How does actinomycin D work?

Answer 37

Intercalating agent (think of the artifacts in the seaweed DNA)

Question 38

Why is bleomycin very useful? How does it work?

Answer 38

Breaks and fragments DNA strands, mainly lethal to cells in the M phase, keeps cells locked in G2 phase Useful because it is detoxified by most tissues except lung and skin (no marrow toxicity)

Question 39

What are the toxicities of concern for bleomycin?

Answer 39

Fibrosis of lung and dermatitis of skin (related to lack of detoxification in lung and skin)

Question 40

What drugs are the anthracyclines and how do they work?

Answer 40

Doxorubicin and daunorubicin -rubicin rubies with Santa Anthracyclin Work by inhibiting topoisomerase II and causing DNA damage, inhibiting synthesis

Question 41

How must doxorubicin be given? Where is it excreted? Active against?

Answer 41

Must be given IV since it is unstable at low pH. Eliminated in liver and bile Active against solid tumors

Question 42

What are the toxicities of the anthracyclines? Is this unexpected?

Answer 42

GI / marrow Most important: Dose-dependent cardiac toxicity due to mitochondrial damage via free radicals -> cumulative effect, and dose-limiting in the longterm Yes -> this was unexpected / unpredictable

Question 43

What are the Vinca alkaloids and how do they work?

Answer 43

Vincristine and Vinblastine Work by binding tubulin dimers and inhibiting formation of microtubules

Question 44

Which vinca alkaloid is highly toxic and what is it used to treat?

Answer 44

Vincristine - highly toxic to peripheral nervous system (unexpected), treats leukemias

Question 45

What is the toxicity of vinblastine?

Answer 45

Marrow toxicity -> used to treat solid tumors

Question 46

What drug works opposite of the vinca alkaloids and stabilizes the microtubules and doesn't allow them to dissociate? What are its adverse effects?

Answer 46

Taxol Can cause neutropenia and hypersensitivity reactions

Question 47

What cell types does Taxol affect?

Answer 47

By inhibiting metaphase and mitosis, it affects rapidly dividing cells

Question 48

What is Topoisomerase 1 vs Topoisomerase 2?

Answer 48

Topoisomerase 1 = 1 strand break, wraps around once, required for DNA unwinding Topisomerase 2 = 1 strand break, pulls one strand through the broken second strand (2 strand effect)

Question 49

What drug is a Topo 1 antagonist?

Answer 49

Camptothecin

Question 50

What drug is a Topo 2 antagonist? What drug is it similar to?

Answer 50

Etoposide Similar to Doxorubicin - works against solid tumors, major toxicity is GI tract and marrow, but NO cardiac toxicity

Question 51

Why can we not simply inhibit the MDR transporter?

Answer 51

Although it would promote drug responsiveness in some tumors, MDR protects many normal host cells from drug toxicity

Question 52

What is tamoxifen?

Answer 52

An anti-estrogen used in the treatment of ER+ breast cancer

Question 53

What are the major reasons for using a drug combination?

Answer 53

1. Can give drugs at lower doses to prevent toxicities in any one system 2. Can circumvent easy resistance mechanism 3. Can kill cells at different stages of cell cycle

Question 54

What drug is used to treat chronic myeloid leukemia (CML)?

Answer 54

Imatinib - TK antagonist Interrupts the constitutively active tyrosine kinase coded for the "Philadelphia chromosome" / translocation 22 by binding to its active site

Question 55

Why are the TK antagonists considered "designer drugs"?

Answer 55

They were rationally developed to sit in the active site of particular tyrosine kinase types within cells (chemistry determined by computer and synthesized by organic chemists)

Question 56

What are Phase 1 vs Phase 2 vs Phase 3 drug trials for cancer?

Answer 56

Phase 1 - test for toxicity Phase 2 - experimental drugs in treatment-resistant patients Phase 3 - experimental drug vs standard therapy

Question 57

What do PARP inhibitors treat and how?

Answer 57

Treat solid tumors by oral administration via inhibition of Poly-adenosine diphosphate polymerases (involved in DNA repair), leading to DNA breaks at replication forks

Question 58

What must be done before giving a monoclonal antibody?

Answer 58

Genetic testing of patient's cancer to make sure the patient's cancer will be susceptible -> only works in a small subset of patients

Question 59

How do checkpoint inhibitors work?

Answer 59

They are molecules which bind on the T cell or on the cancer cell and prevent T-cell / cancer cell co-regulation which would normally help the cancer evade T cell response i.e. PD-1 + PD-L1 for evasion of apoptosis

Question 60

How does ipilimumab work?

Answer 60

Binds the PD-1 site on T cells to prevent PD-1 / PD-L1 interaction (there are also drugs which target PD-L1 on tumor cells)

Question 61

What type of tumors are monoclonal antibodies and checkpoint inhibitors generally given for?

Answer 61

Slow-growing tumors to improve outcomes

Question 62

How are all antimetabolites excreted?

Answer 62

Kidney

Question 63

How are all natural products excreted?

Answer 63

Bile / liver