Pharmacology Antineoplastics Antimetabolites/antibiotics Spring 2011

Front 1

Three types of antimetabolites?

Back 1

1. Folic acid analogs
2. Pyrimidine analogs
3. Purine analogs

Front 2

Folic Acid Analogs?

Back 2

Methotrexate
Trimetrexate (PCP)

Front 3

Pyrimidine analogs?

Back 3

5-Flurouracil
Capecitabine
Cytarabine

Front 4

Purine Analogs?

Back 4

Mercaptopurine
Fludarabine
Cladribine
Thioguanine
Pentostatin (Hairy cell leukemia)

Front 5

General notes on antimetabolites

Back 5

Structural analogs of naturally occurring bases to inhibit enzymes or substitute

Cytotoxic effects during S phase and impaired synthesis in G1 phase

Front 6

Antimetabolites resistance formed via?

Back 6

Gene amplification of inhibited enzymes

Making enzymes that have less affinity for drug

Front 7

Methotrexate works by? Also used in?

Back 7

folic acid analog with high affinity for dihydrofolate reductase

Also used in rheumatoid arthritis, lupus, transplants

Front 8

How does MTX get into cells?

Back 8

actively transported into cells (moreso into cancer cells) and then polyglutamate synthetase adds glutamyl residues to trap MTX into cells

Leucovorin is given to be taken into healthy cells so that they can make folic acid normally

Front 9

MTX used in?

Back 9

Oral and IV for

Acute lymphoblastic leukemia, bladder, breast, CNS lymphomas

Inhibits cell-mediated immune reactions

Front 10

MTX toxcity?

Back 10

Ulceration
Marrow suppression
N/V
Alopecia
Hepaotox
Teratogenic
*Actively secreted into proximul tubule so can interact with other things that are secreted

BBW: preg, hepatic disease, pulmonary disease, infections

Front 11

Pemetrexed MOA? used in? Special tox?

Back 11

MOA: converted to poly-glutamated form, rapidly transported to inhibit Thymidylate synthetase and Dihydrofolate synthetase

For: mesothelioma, lung cancer, better for colon cancer than MTX

S/E: pruritic rash, severe marrow suppression, neuropathy

Front 12

Pyrimidine analogs:

Back 12

5-Fluorouracil
Cytarabine

Front 13

MOA of 5-FU

Back 13

5-FU attached to ribose to make fdUMP which can displace dUMP to inhibit thymidine for DNA synthesis and RNA synthesis

Front 14

Leucovorin use in MTX vs 5-FU

Back 14

In MTX Leucovorin is used to save the non-cancer cells and help them make folic acid

With 5-FU leucovorin is used to potentiate the toxicity

Front 15

Describe how 5-FU is given, Why?

Back 15

5-FU is used both intraarterially and topically
Infused over 5 days to get cells into S phase

*Cell cycle specific

Front 16

5-FU most used for?

Back 16

Slow growing solid tumors

Front 17

Floxuridine is?

Back 17

FU + deoxyribose (FUdR)

Front 18

Floxuridine used for? given via?

Back 18

Used for metastatic carcinoma in liver, given via hepatic artery

Front 19

Capecitabine is?

Back 19

Prodrug of FUdR

for nonresponsive metastatic breast cancer

Front 20

5-FU specific S/E? (along with common)

Back 20

Hand-foot syndrome - pain and sensitivity of palms and soles

Front 21

Cytarabine is what?

Back 21

Cytosine plus D-arabinose sugar (OH in the wrong orientation so blocks next base pair)

Front 22

Cytarabine MOA?

Back 22

inhibits DNA polymerase leading to unbalanced growth

Incorporated into DNA to inhibit elongation

Front 23

Cytarabine given how?

Back 23

IV over 5 - 7 days to phase cell cycle (get into S phase)

Front 24

Cytarabine used for?

Back 24

AML, CML, CLL (i.e. Leukemia)

Front 25

Cytarabine tox?

Back 25

Potent myelosuppression
Ulceration

Front 26

Gemcitabine MOA?

Back 26

is a Difluroanalogue of cytidine incorporated into DNA to terminate strand

Front 27

Gemcitabine used for?

Back 27

metastatic cancers

given every 7 days

Front 28

Gemcitabine tox?

Back 28

Flu-Like syndrome, potent radiation sensitizer, dyspnea

Front 29

Purine Analogs for what?

Back 29

Adenine and Guanine

Front 30

Name Purine Analogs

Back 30

6-Mercaptopurine
Thioguanine
Fludarabine
Cladribine

Front 31

6-Mercaptopurine MOA

Back 31

6-MP is phosphorylated and added to sugar to form thio-IMP which will inhibit Hypoxanthine-guanine phosphoribosyl transferase to inhibit xanthine and adenosine

Prevents DNA and RNA synthesis

Front 32

6-Mercaptopurine used for?

Back 32

Oral and IV for

Leukemias

Front 33

6-MP metabolized by?

Back 33

Two pathways:
P-450
Xanthine oxidase

Front 34

what consequence with 6-MP?

Back 34

hyperuricemia so give Allopurinol given to increase 6-MP levels and decrease uric acid levels

Front 35

6-MP Tox?

Back 35

Long term hepatotox
OIs
hematological suppression

Front 36

Thioguanine used in? Tox?

Back 36

Used in leukemias

S/E: hematological suppression

Front 37

Fludarabine used in? Tox?

Back 37

Used in leukemias and lymphomas

S/E: N/V bone marrow suppression

Front 38

Cladribine used in?

Back 38

hair cell leukemia, CML, ALL

Front 39

Antibiotics used in cancer therapy

Back 39

Dactinomycin
Daunorubicin
Doxorubicin
Bleomycin

Front 40

Daunorubicin and Doxorubicin used in?

Back 40

Hematological and solid tumors

Front 41

Bleomycin used in?

Back 41

Testicular, head, neck, cervical, Hodgkin's lymphomas, sarcoma's

Front 42

General MOA of ATBs in chemo?

Back 42

MOA: Directly bind DNA or intercalate between DNA base pairs preventing replication

Physically prevent replication

Front 43

Dactinomycin used in?

Back 43

Ewings
Wilm's

Front 44

Dactinomycin MOA? notes?

Back 44

intercalates DNA causing ss breaks

One of the most potent tumor agents

Front 45

Dactino used in?

Back 45

rhabdomyosarcoma
Wilm's tumor

Front 46

Dactino tox?

Back 46

Pancytopenia, GI effects

Front 47

Dauno and Doxo MOA?

Back 47

Intercalate into DNA,
preventing uncoiling,
inhibiting Topoisomerase II

Front 48

Possible MOA of cardiotox of Dauno and Doxo

Back 48

Will also bind to cell membranes to alter IP3 activation

Cardiac tissue is low in superoxide dismutase and catalase so are affected by radicals

Front 49

Dauno and Doxo form a ____ intermediate that may?

Back 49

Semiquinolone intermediate that forms free radicals that can cause DNA damage and breaks

Front 50

Dauno used in?

Back 50

AML

Front 51

Doxo used in?

Back 51

many things, wider range

breast, bladder, lung, ovarian, testicular, thyroid, ALL, lymphomas..

Front 52

Dauno and Doxo tox?

Back 52

usual +
Cardiac toxocity! -- there is a life dose (Doxo is 550)
Discoloration of urine! (red)
Severe vesiant properties
Secondary leukemias

Front 53

Can give what to decrease superoxide?

Back 53

Dexarzoxane to prevents free radicals
Lipid complexes which aren't taken into the cell

Front 54

Idarubicin used in?

Back 54

leukemias

Front 55

Idarubicin tox?

Back 55

less cardiotox
red urine

Front 56

Epirubicin used in?

Back 56

multiple; bladder, breast, head and neck, lung ovarian

Front 57

Epirubicin tox?

Back 57

cardiac tox
red urine

Front 58

Valrubicin used in?

Back 58

bladder tumors
Resistant bladder tumors

Front 59

Valrubicin tox?

Back 59

teratogenic (as all are)
red urine

Front 60

Mitoxantrone analog of?

Back 60

Doxorubicin

Front 61

Mitoxantrone used in?

Back 61

AML, CLL, breast, ovarian

Front 62

Mitoxantrone tox?

Back 62

less cardio tox, less bone marrow suppression
sexual dysfunction
blue-green urine and nails
not as much vesicant

Front 63

Mitoxantrone also used in?

Back 63

Progressing MS

Front 64

Bleomycin MOA?

Back 64

can intercalate into DNA and the metal binding core will complex with Fe and Cu, will also form free radicals

Front 65

Bleomycin cell cycle specific?

Back 65

Yes; for G2 phase

Front 66

Bleomycin used in?

Back 66

multiple: cervical, pancrativ, Hodgkin's, sarcoma

ABVD for Hodgkin's

Front 67

Bleomycin tox?

Back 67

low myelosuppression
Dry cough==> pulmonary fibrosis
flu-like
skin reactions

Front 68

Bleomycin also used third line in?

Back 68

topically for wart removal

Front 69

Mitomycin MOA?

Back 69

alkylation, free radicals

Front 70

Mitomycin used in?

Back 70

many: head and neck, soft tissue sarcoma, metastatic bone, stomach

Front 71

Mitomycin tox?

Back 71

SEVERE bone marrow tox (wait 8 weeks between treatments)
pulmonary tox
secondary leukemias