Chemotherapy

Question 1

What are side effects of chemotherapy drugs?

Answer 1

1. Bone Marrow (G-CSF shorten period of Leukopenia)
2. Healing - weak
3. Alopecia
4. Damage to gastrointestinal epithelium (nutritional state)
5. Depression of growth (children)
6. Sterility
7. Teratogenicity
8. Severe nausea (treat with 5-HT3-receptor antagonist)

Question 2

What is cachexia?

Answer 2

• a certain percentage of cancer patients look emaciated
• suggesting that this is regulated by TNFa combined with poor gastrointestinal agents caused by chemo agents.

Question 3

How does aspiriginase work?

Answer 3

• Used in lymphoblastic cancers

1. Cancer cells cannot make aspirigine so it is essential AA for them but we can make it
2. Aspiriginase converts L-asparagine to L-aspartic acid
3. Depletes aspirigine stores :. lymphoblasts die

Problem: short half life so you have to regulate it as its half life can add immunity against it

Question 4

What are the active parts of alkalyating agents?

Answer 4

Carbonium ion - binds to guanine and forms cross links :. can kill cell

Question 5

What other effects do alkylating agents have?

Answer 5

1. Ring cleavage
2. Abnormal base pairing (G-T)
3. Guanine excision from DNA
4. Protein interactions

NB. Non-selective so can kill normal cells

Question 6

How is cyclophoshamide activated?

Answer 6

Activate in liver to make acrolein and the active component: phosphate mustard (2 carbonium ions)

When platin is in water has similar effect

Question 7

What is the mechanism of resistance of alkylating agents?

Answer 7

1. Decreased permeability
2. Increased production of glutathione (stops damage to DNA)
3. Increase DNA repair
4. Increased metabolism of drugs (pump out drugs)

Question 8

How is cis-platin administered and what is it used for?

Answer 8

1. I.V.
2. testes and ovaries cancer

Question 9

How does methatroxate work?

Answer 9

1. Taken by cells and converted by addition of protons in two reactions by dihydrofolate reductase causing formation of dihydromethatroxate
2. Normally folate version is cofactor for thymidylate synthase
3. But the methatroxate version interacts with TS it inhibits TS
4. :. cannot get internucleoside conversion

Question 10

What is the mechanism of resistance for methotrexate?

Answer 10

1. Decreased transport into cells
2. Decreased affinity of DHF reductase :. so can’t recognise methotrexate
3. Increased levels of DHF reductase :. overcoming inhibitory effects

Question 11

How is methotrexate administered and what is it used for?

Answer 11

1. IV or oral
2. Non-hodgink’s lymphoma
3. Burkitt’s lymphoma
4. Childhood acute ALL

Question 12

How does 5-fluorocil work?

Answer 12

1. Analogue of uracil
2. Using thymidine phosphorylase combines with nucleoside
3. Fluorine group on carbon stops methylation :. thymidilate synthase cannot work to make nucleotide (also complexes with tetrahydrofolate to inhibit thymidilate synthase)

Question 13

How does 5-fluorouracil develop resistance?

Answer 13

1. Decreased levels of thymidine phosphorylase
2. Decreased affinity for 5FU

Question 14

How is 5-fluorouracil administered?

Answer 14

1. Parentally
2. Breast, ovarian, prostate, pancreatic, hepatic carcinomas

Question 15

How do cytarabine and cytosine arabinoside work?

Answer 15

1. Have OH group :. prevents DNA elongation

Question 16

What are the mechanisms of resistance of cytarabine and cytosine arabinose?

Answer 16

1. Decreased levels of deoxycytidine kinase
2. Increase in dCTP

Question 17

How is cytarabine and cytosine arabinose administered?

Answer 17

1. Oral or IV
2. Chronic granulocytic leukemia

Question 18

How do doxorubicin work and dactomycin work?

Answer 18

1. Bind and stabilise topoisomerase II (DNA gyrase)
2. DNA stays open
3. Can be attacked by oxidation species

Question 19

How doe etoposide work?

Answer 19

Inhibits DNA topoisomerase

Question 20

What are the mechanisms of resistance of doxorubicin and dactinomycin?

Answer 20

1. Pumping drug out
2. Increased glutathione peroxidase
3. Decreased topoisomerase

Question 21

How are doxorubacin and dactinomycon administered?

Answer 21

1. IV
2. ALL
3. AGL

Question 22

How do dactomycin and bleomycin work?

Answer 22

1. Bind to minor and major groove respectively
2. Collates iron
3. Partakes in fenton reactions which attack DNA

NB. Only drug which works on cells that are in G0

SE: can cause pulmonary fibrosis = fatal

Question 23

What are the resistance mechanisms of dactinomycin and bleomycin and what are they used for/administered?

Answer 23

Resistance

1. Increase anti-oxidant
2. Increase DNA-repair mechanisms
3. Parentally administed
4. Treatment of testicular and ovarian cancer

NB. Dactinomycin is used with other modalities

Question 24

How do vincristine, vinblastine and vindesine work?

Answer 24

1. Block assembly of microtubules

Resistance:

1. multidrug resistance
2. altered tublin molecules

Administered:

1. IV
2. Childhood leukemia’s
3. Hodgkin’s
4. non-Hodgkin’s lymphoma, testicular, ovarian carcinomas and brain tumours

Question 25

What does Taxol (paclitaxet) do?

Answer 25

1. Binds and stabilised microtubules 2. Means gets longer until cells die _Resistance_ 1. altered tublin molecules Administered: 1. i.v. 2. Metastatic ovarian (imp) and breast cancer

Question 26

How does bortezomib do?

Answer 26

1. proteosome inhibitor 2. NFkB is imp. trasncription factor and also anti-apoptic and in some tumours like multiple myeloma this is upregulated and keeps the activity going, can 3. increase the conc. of natural inhibuor called Ikb but because Ikb is broken down by proteosome, the protesome is inhibited which prevents breakdown of inhibitor which means can remove the anti apoptotic effects

Question 27

What is bortezomib used for?

Answer 27

Multiple myeloma