Block 6 - German Lectures

Question 1

Which phase of cancer is the last one that is reversible with diet and lifestyle changes?

Answer 1

Promotion

Question 2

What are the 3 classifications of anti-cancer drugs?

Answer 2

Immunotherapy

Chemotherapy

Hormonal therapy

Question 3

Drugs that are directed against tumor DNA have 3 different MOAs. List them and give an example.

Answer 3

• break the helix itself (cross-linkers)
• interfere with DNA-related proteins (topoisomerase inhibitors)
• modify the expression of genes (alkylating and methylating agents)

Question 4

Which form of cross-linking can be easily removed?

Answer 4

Intrastrand (on the same strand)

Question 5

The common site of attack for DNA cross linking is

Answer 5

the 7-position N of guanine

Question 6

What much DNA alkylating agents contain (structurally speaking)?

Answer 6

must have electrophilic centers with good leaving groups

• the general structure is an R group with the central molecule (electrophile) attached to two leaving groups

Question 7

Why do alkylating agents cause toxicity?

Answer 7

They are non-selective for cancer cells and will attack all rapidly dividing cells (like the skin)

Question 8

What issue arises with the use of ifosfamide?

Answer 8

It is a prodrug with two different isomers (S and R).

The S isomer is responsible for the formation of the actual alkylating agent (aziridine)

The R form causes nephrotoxicity because it can be converted to chloroacetaldehyde in the nephrons.

Question 9

What is the actual alkylating agent made from the prodrug ifosfamide?

Answer 9

Aziridine

Question 10

Which alkylating agent’s toxicity can be treated using an adjunct therapy of mesna?

Answer 10

Cyclophosphamide. It’s main toxicity comes from acrolein and CAA.
Acrolein can be counted with mesna because mesna (injected in the active form and selectively reduced in the kidney) will concentrate in the bladder and scavenge acrolein.

Question 11

What are the important points to remember about platinum compounds?

Answer 11

• Platinum is electron deficient
• must be stabilized by amino acids to prevent it from reacting with everything
• NH3 act as stabilizing groups and chloride ions make for good leaving groups
• when it cross-links the DNA in the cis configuration it cannot be repaired by the cells
• side effects include nephrotoxicity, emetogenesis, and neurotoxicity (limiting factor in use)

Question 12

Which drugs are intercalting agents?

Answer 12

anthracycline
etoposide (topo 2 inhibitor)
irinotecan (topo 1 inhibitor)
topotecan (topo 1 inhibitor)

Question 13

Which drugs are S phase specific?

Answer 13

Topoisomerase inhibitors (specificaly topo 1)
DNA chain terminators 

Note - topo 2 inhibitors can act during early G2

Question 14

Why do irinotecan and topotecan have basic side chains on C10 and C9, respectively?

Answer 14

To increase water solubility

Question 15

What side effect is characteristic of all intercalating agents?

Answer 15

Myelosuppression

Question 16

What is unique about teniposide (a topo 2 inhibitor) that makes it more potent than other drugs of its class?

Answer 16

it has a tienyl moiety (sulfur) that increases its lipophilicity, thus increasing its uptake and potency

Question 17

Which kind of topoisomerase inhibitor is able to bind to either the topo-DNA complex or the topoisomerase itself?

Answer 17

Topoisomerase 2 inhibitors

Question 18

Which topoisomerase 1 inhibitor causes diarrhea?

Answer 18

Irinotecan

Question 19

What must all intercalators have in their structure?

Answer 19

Need large (usually multiple rings) planar (flat) surfaces so they can fit between pairs of DNA

Question 20

Why are anthracyclines called antitumor antibiotics?

Answer 20

Because they’re isolated from microorganisms and used to treat cancer.

Question 21

Which stage of the cell cycle are anthracyclines specific to?

Answer 21

G2

Question 22

How do anthracyclines cause cardiotoxicity? How can it be mitigated?

Answer 22

They form superoxide radicals and hydroxide radicals.
The hydroxide radicals are formed through the Fenton reaction, and cardiac tissues don’t have enough catalases or cytoprotective enzymes.
The solution is to co-administer an antioxidant and an iron chelator.

Question 23

Why do anthracyclines have “rubicin” as the suffic?

Answer 23

They turn urine red.

Question 24

What makes epirubicin less toxic than doxorubicin?

Answer 24

The 4’-hydroxy group on epirubicin is in the beta position and thus less prone to one-electron oxidation