Fitzpatrick - Anti-Neoplastic Drugs, Alkylating Agents CCNSD

Question 1

Cell cycle specific drugs are dependent on what?

Answer 1

Schedule dependent - Duration and timing of drug administration affect efficacy&raquo_space;> dose dependent

Question 2

DNA alkylating/cross-linking agents: MOA

Answer 2

• MOA - attack nucleophiles (-06, -07 N7 position of guanine)
• Damage - crosslinking (bifunctional) or alkylating (monofunctional)
• Consequences - miscoding of DNA bases, DNA breakage

Question 3

Name repair sensitive G-G crosslinks.

Answer 3

N-mustards, thiotepa, busulfan

Question 4

Name repair sensitive G-C crosslink.

Answer 4

Chloroethylnitrosoureas

Question 5

Name repair insensitive G-G crosslink.

Answer 5

Mitomycin

Question 6

Name repair sensitive G-CH3 (O6-G-methylation).

Answer 6

Dacarbazaine, procarbazine, temozolomide

Question 7

Cell cycle non-specific drugs are dependent on what?

Answer 7

Efficacy weighed more heavily on Dose Dependent&raquo_space;> schedule

Question 8

Therapeutic use for mechlorethamine

Answer 8

Hodgkin Disease (MOPPS)

Question 9

Adverse effect of mechlorethamine.

Answer 9

Blisters, necrosis if extravasation occurs. Occurs bc instantaneous activation by water upon infusion.

Question 10

Cyclophosphamide activation in ___ location via ___ enzyme.

Answer 10

In liver via CYP450 activation.

Question 11

Metabolites of Cyclophosphamide (two).

Answer 11

• Acrolein = urotoxic (bladder)

- Phosphoramide Mustard = active tumor metabolite drug

Question 12

Ifosfamide activation in ___ location via ___ enzyme.

Answer 12

In liver via CYP450 activation and CYP2B6/CYP3A4.

Question 13

Metabolites of ifosfamide (three).

Answer 13

• Acrolein = urotoxic (bladder)
• Phosphoramide Mustard = active tumor metabolite drug
• Chloracetaldehyde (CYP2B6/CYP3A4) = NEUTROTOXICITY - seizures, paralysis, coma

Question 14

Dose limiting toxicity of nitrosoureas.

Answer 14

myelosuppression

Question 15

A person has brain cancer - what class of Alkylating agents should be used and why?

Answer 15

bc they penetrate/have Good distribution in the CNS.

• Carmustine (Nitrosoureas) limited to brain cancer
• Temozolomide (triazene) - refractory anaplastic astrocytoma and glioblastoma

Question 16

MOA of dacarbazine and temozolomide

Answer 16

• Dacarbazine - IV w/ CYP4501A activation
• Temozolomide - PO; spontaneous H+

Both result in activated metabolite MTIC –> electrophile (CH3)

Question 17

What triazene DOES NOT penetrates the CNS effectively?

Answer 17

Dacrabazine

Question 18

Status of O^6 MGMT has what effects on temozolomide alkylating DNA

Answer 18

• High MGMT = DNA repair nullifies damage - refractory

- Low MGMT = susceptible dt catastrophic DNA damage = GOOD

Question 19

How does cisplatin/related compounds enter cells to cross link?

Answer 19

Enter via diffusion and Cu2+ transporter

Question 20

1/2 of cisplatin is excreted in urine in 24hrs, so ____ location has a greater concentration of platinum than plasma and other organs, thus causing ____.

Answer 20

Renal cortex

NEPHROTOXICITY

Question 21

MOA of cisplatin resistance.

Answer 21

1. Decreased uptake or increased efflux.
2. Neutralization of cisplatin by GLUTATHIONE
3. Increased DNA repair
   4 Defective apoptosis

Question 22

10 days after ___ drug administration, lower GFR, higher serum Cr, reduced serum Mg and K levels = ____

Answer 22

Cisplatin administration

Cisplatin nephrotoxicity (can also be secondary to tumor lysis syndrome)

Question 23

oxaloplatin toxicity

Answer 23

neutropenia, cold induced neurpathy