Disrupt DNA & Antimitotics- Fitz Flashcards Preview

IHO WEEK 3 > Disrupt DNA & Antimitotics- Fitz > Flashcards

Flashcards in Disrupt DNA & Antimitotics- Fitz Deck (35):
1

Describe MOA in general for cross linking agents

Activation- must be, or become strong electrophiles

Attack on cell nucleophiles (N7 position of guanine)

Cause DNA damage:
Crosslinking
Miscoding of DNA bases
DNA strand breakage

2

How do crosslinking agents demonstrate selective toxicity?

DNA damage normally activates a check point in cell cycle that is dependent on p53

most cancers do not have this, so cannot repair DNA

Normal cells stop cell cycle and repair the damage

3

What are common resistance mechanisms to crosslinking agents?

Increased production of nucleophilic substances

Increased DNA repair

Decreased activation

4

Are alkylating agents susceptible to multidrug resistance?

YES!!! If cells adapt to one alkylating agent, they will be less susceptible to other alkylating agents

5

What happens instantaneously when mechlorethamine is in contacted with H20?

It is activated to a strong electrophile

Causing blistering/burning (vesicant)

Also most emetic!!!

6

What is a unique toxicity associated with cyclophosphamide?

Hemorrhagic cystitis!!!

It is a derivative of mechlorethamine

Activated by liver CYP450 enzyme

Final activation produces phosphoramide mustard (active drug) and Acrolein

Acrolein causes the hemorrhagic cystitis

Treat with MESNA

7

What do you treat hemorrhagic cystitis from cyclophosphamide with?

MESNA!

8

What differentiate Ifosfamide from cyclophosphamide?

Ifosfamide is slower acting, more broad, and the MOST NEUROTOXIC of all alklyating agents

9

What is the MOA of melphalan? What is it used to treat? And how is administered?

Alkylating Agent
Given orally
Used to treat Multiple Myeloma

10

What is carmustine/lomustine usually used to treat?

Alkylating Agent
BRAIN TUMORS!!
Highly lipid soluble
Toxicities to lung and liver

11

What is busulfan used to treat? What are the major side effects?

Alkylating Agent
Used to treat chronic myeloid leukemia

Toxicities= Hyperpigmentation, lung, and hepatotoxicity

12

MOA of chlorambucil?

Alkylating agent
Given orally
Lung toxicity

13

What is temozolamide used to treat and why?

Brain tumors!!! Highly fat soluble

14

What type of drug is cisplatin (carboplatin, oxaloplatin)?

Platinum Analogues- Alkylating agents

15

Toxicity of cisplatin?

Most potent EMETIC!!!
Kidney toxicity
Ototoxic
Peripheral neuropathy

16

MOA of mitomycin?

Undergoes metabolic activation to become alkylating agent

Antibiotic

17

MOA of doxorubicin?

Anthracycline antibiotic
Intercalates major grooves of DNA - leads to inhibition of TOPO II- causes double/single strand breaks

18

Forms of resistance to doxorubicin

INCREASE P-GLYCOPROTEIN!!! (multidrug resistance)
Changes in target protein = dereased TOPO II activity

Increased inactivation through increased glutathion peroxidase = protection against oxidative damage

19

Therapeutic uses of doxorubicin

boradest spectrum antineoplastic agents

Hodgkins, and breast cancer

one of the most commonly used antineoplastic agents

20

What is the unusual and irreversible side effect related to doxorubicin?

CARDIOMYOPATHY
irreversible, and related to TOTAL dose of drug

21

What are other side effects related to doxorubicin besides cardiomyopathy?

extravasation- necrosis
Myelopsuppression
Radiaton Recall reaction
Hand-foot syndrome
Red Urine - due to chemical reaction

22

What is the radiation recall reaction?

erythema and desquamation of the sin at sites of prior radiation therapy

23

What is the MOA for bleomycin?

Binds to DNA (not RNA) through its amino-terminal peptide, and generates free radicals that cut the DNA

24

What are the two mechanisms of resistance for bleomycin?

Increased inactivation - increased hydorlase activity

Increased DNA repair

25

What is the MOA of Etoposide?

Forms complex with topo II and DNA that results in DOUBLE-strand breaks- remains bound to enzyme so that repair cannot occur

26

What are the two main mechanisms of resistance for Etoposide?

Decreased accumulation via increased p-glycoprotein

Mutation or decreased expression of topo II or decreased apoptosis due to mutation in p53

27

What is MOA of Irinotecan and topotecan?

Inhibitor of TOPO I and causes SINGLE strand breads

28

What is the BIG difference in elimination between Irinotecan and topotecan?

Irinotecan - eliminated by LIVER
Topotecan - eliminated by KIDNEY

29

Main forms of resistance of Irinotecan/topotecan?

Decreased activation
Decreased accumulation via increased P-glycoprotein

30

What is the MOA of for Vinlastine/Vincristine?

Bind to tubulin at the forming end of the microtubules and TERMINATE (disrupt) spindle assembly

31

What is the main difference in toxicities between vinlastine and vincristine?

Vinlastine- bone marrow suppression

Vincristine- CNS toxicity, fatal if given intrathecally (mainly because of the requirement for microtubules in axon transport)

32

What is the mechanism of paclitaxel?

Binds to tubulin and ENHANCES and STABILIZES spindle assembly

33

Main mechanism of resistance for paclitaxel?

Decreased accumulation via increased P-glycoprotein expression

34

What is the MOA for ixabepilone?

Antibiotic that binds to tubulin and ENHANCES and STABILIZES spindle assembly (similar to paclitaxel)

35

What are some common toxicities of ixabepilone?

Bone marrow suppression
Peripheral neuropathy
Caridac Arrythmias
Hypersensitivites