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Flashcards in Anti-Tumor Pharmacology Deck (63):
1

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

Lung cancer

2

Why is chemotherapy needed on top of surgery?

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

3

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

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)

4

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

Rapidly dividing cells in the human:

i.e. GI tract, bone marrow

5

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

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

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

6

What are examples of slow-growing tumors?

Lung, breast, colon

>80 day doubling, 5% growth fraction

7

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

Angiogenesis

8

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

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

9

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

Give near-maximum tolerated levels

10

What drives the selective toxicity of alkylating agents?

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

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?

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

12

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

the CNS

13

How are non-cycle specific drugs given?

I.e. alkylating agents or antibiotics

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

14

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

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

15

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

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

16

How does methotrexate work?

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

17

What is the most common mechanism of methotrexate resistance?

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

18

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

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

19

How is MTX excreted and why does this matter?

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

20

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

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

21

How does 5-FU resistance develop?

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

22

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

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

23

What is FU used to treat? Why?

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

24

What is the mechanism of action of cytosine arabinose?

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

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

25

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

Ara-C - effectively treats acute leukemias as it is not self-limiting

High dose - irreversible CNS damage

Typical: GI tract / marrow suppression

26

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

Acute leukemias

Requires phosphorylation like Ara-C and is a guanine analog

27

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

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.

28

What is the most lethal effect of alkylating agents?

The cross-linking of DNA

29

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

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

30

What tumors does cyclophosphamide (CTX) treat?

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

31

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

Hemorrhagic cystitis / bladder cancer

Reversed via administration of MESNA which can neutralize the metabolites in bladder

32

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

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

Used for brain tumors

33

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

Crosslinks DNA

Used against solid tumors like testicular / ovarian cancer

34

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

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

35

What is the most likely defense mechanism against alkylating agents?

Enhanced DNA repair after alkylation

36

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

Multi-drug resistance transporter (MDR)

37

How does actinomycin D work?

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

38

Why is bleomycin very useful? How does it work?

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)

39

What are the toxicities of concern for bleomycin?

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

40

What drugs are the anthracyclines and how do they work?

Doxorubicin and daunorubicin
-rubicin rubies with Santa Anthracyclin

Work by inhibiting topoisomerase II and causing DNA damage, inhibiting synthesis

41

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

Must be given IV since it is unstable at low pH.

Eliminated in liver and bile

Active against solid tumors

42

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

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

43

What are the Vinca alkaloids and how do they work?

Vincristine and Vinblastine

Work by binding tubulin dimers and inhibiting formation of microtubules

44

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

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

45

What is the toxicity of vinblastine?

Marrow toxicity -> used to treat solid tumors

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?

Taxol

Can cause neutropenia and hypersensitivity reactions

47

What cell types does Taxol affect?

By inhibiting metaphase and mitosis, it affects rapidly dividing cells

48

What is Topoisomerase 1 vs Topoisomerase 2?

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)

49

What drug is a Topo 1 antagonist?

Camptothecin

50

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

Etoposide

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

51

Why can we not simply inhibit the MDR transporter?

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

52

What is tamoxifen?

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

53

What are the major reasons for using a drug combination?

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

54

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

Imatinib - TK antagonist

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

55

Why are the TK antagonists considered "designer drugs"?

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)

56

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

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

57

What do PARP inhibitors treat and how?

Treat solid tumors by oral administration

via inhibition of Poly-adenosine diphosphate polymerases (involved in DNA repair), leading to DNA breaks at replication forks

58

What must be done before giving a monoclonal antibody?

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

59

How do checkpoint inhibitors work?

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

60

How does ipilimumab work?

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)

61

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

Slow-growing tumors to improve outcomes

62

How are all antimetabolites excreted?

Kidney

63

How are all natural products excreted?

Bile / liver