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Pharmacology > Anti-Tumor Pharmacology > Flashcards

Anti-Tumor Pharmacology Flashcards

1
Q

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

A

Lung cancer

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2
Q

Why is chemotherapy needed on top of surgery?

A

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

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3
Q

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

A

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)
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4
Q

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

A

Rapidly dividing cells in the human:

i.e. GI tract, bone marrow

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5
Q

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

A

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

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

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6
Q

What are examples of slow-growing tumors?

A

Lung, breast, colon

> 80 day doubling, 5% growth fraction

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7
Q

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

A

Angiogenesis

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8
Q

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

A

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

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9
Q

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

A

Give near-maximum tolerated levels

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10
Q

What drives the selective toxicity of alkylating agents?

A

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

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11
Q

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?

A

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

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12
Q

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

A

the CNS

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13
Q

How are non-cycle specific drugs given?

A

I.e. alkylating agents or antibiotics

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

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14
Q

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

A

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

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15
Q

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

A
  1. Methotrexate - does not require phosphorylation
  2. 5-Fluorouracil
  3. 6-Mercaptopurine
  4. Cytosine arabinose
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16
Q

How does methotrexate work?

A

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

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17
Q

What is the most common mechanism of methotrexate resistance?

A

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

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18
Q

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

A

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

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19
Q

How is MTX excreted and why does this matter?

A

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

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20
Q

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

A

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

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21
Q

How does 5-FU resistance develop?

A

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

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22
Q

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

A

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

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23
Q

What is FU used to treat? Why?

A

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

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24
Q

What is the mechanism of action of cytosine arabinose?

A

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

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

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25
Q

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

A

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

High dose - irreversible CNS damage

Typical: GI tract / marrow suppression

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26
Q

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

A

Acute leukemias

Requires phosphorylation like Ara-C and is a guanine analog

27
Q

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

A

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
Q

What is the most lethal effect of alkylating agents?

A

The cross-linking of DNA

29
Q

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

A

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
Q

What tumors does cyclophosphamide (CTX) treat?

A

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

31
Q

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

A

Hemorrhagic cystitis / bladder cancer

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

32
Q

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

A

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

Used for brain tumors

33
Q

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

A

Crosslinks DNA

Used against solid tumors like testicular / ovarian cancer

34
Q

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

A

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
Q

What is the most likely defense mechanism against alkylating agents?

A

Enhanced DNA repair after alkylation

36
Q

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

A

Multi-drug resistance transporter (MDR)

37
Q

How does actinomycin D work?

A

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

38
Q

Why is bleomycin very useful? How does it work?

A

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
Q

What are the toxicities of concern for bleomycin?

A

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

40
Q

What drugs are the anthracyclines and how do they work?

A

Doxorubicin and daunorubicin
-rubicin rubies with Santa Anthracyclin

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

41
Q

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

A

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

Eliminated in liver and bile

Active against solid tumors

42
Q

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

A

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
Q

What are the Vinca alkaloids and how do they work?

A

Vincristine and Vinblastine

Work by binding tubulin dimers and inhibiting formation of microtubules

44
Q

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

A

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

45
Q

What is the toxicity of vinblastine?

A

Marrow toxicity -> used to treat solid tumors

46
Q

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

A

Taxol

Can cause neutropenia and hypersensitivity reactions

47
Q

What cell types does Taxol affect?

A

By inhibiting metaphase and mitosis, it affects rapidly dividing cells

48
Q

What is Topoisomerase 1 vs Topoisomerase 2?

A

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
Q

What drug is a Topo 1 antagonist?

A

Camptothecin

50
Q

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

A

Etoposide

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

51
Q

Why can we not simply inhibit the MDR transporter?

A

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

52
Q

What is tamoxifen?

A

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

53
Q

What are the major reasons for using a drug combination?

A
  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
Q

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

A

Imatinib - TK antagonist

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

55
Q

Why are the TK antagonists considered “designer drugs”?

A

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
Q

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

A

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

57
Q

What do PARP inhibitors treat and how?

A

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
Q

What must be done before giving a monoclonal antibody?

A

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
Q

How do checkpoint inhibitors work?

A

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
Q

How does ipilimumab work?

A

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
Q

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

A

Slow-growing tumors to improve outcomes

62
Q

How are all antimetabolites excreted?

A

Kidney

63
Q

How are all natural products excreted?

A

Bile / liver

Pharmacology (54 decks)

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