Cancer drug discovery and development

Question 1

What is camptothecin

Answer 1

A plant extract which has a unique structure of alpha-hydroxylactone alkaloid

It is active against leukaemia cells and solid tumour inhibition

Question 2

What is the important group of camptothecin activity

Answer 2

Lactone group- adding substituents onto the ring can change the binding affinity

Question 3

What is the mechanism of action of camptothecin

Answer 3

Inhibition of topoisomerase I that is implemented in DNA transactions like topoisomerase importance, replication, transcription and recombination

Question 4

What are the two new derivatives of camptotheicin

Answer 4

1. Irinotecan: has reduced toxicity and is used to treat metastatic colorectal cancer and effective against lung cancer and leukaemia
2. Topotecan: metastatic ovarian cancer, a prodrug that is a phenolic T-1 inhibitor (salts can be made)

Question 5

What is taxol and how is it made

Answer 5

Anticancer agent made from stem bark that is active against solid tumours and leukaemia models and melanoma

Question 6

What are the taxol functional groups present and which is the most important

Answer 6

Hydroxyl, ketone, ester, amide, aliphatic chains

IMPORTANT:
Oxytane (ring with oxygen)
C-13 ESTER GROUP is essential for anti tumour activity

Question 7

What is the mechanism of action of taxol

Answer 7

Taxol inhibited by mitosis

Stabilises microtubules and inhibited depolymerisation back to tubulin

Question 8

How was the initial problem of using the taxol plant solved

Answer 8

Conversion of metabolites present in larger amounts in the needles (renewable source)

Question 9

What is taxols other name and what is it used for

Answer 9

Paclitaxel

Ovarian cancer, second treatment to breast cancer and NSC cancers

Question 10

What is a semi synthetic approach

Answer 10

Isolating a biosynthetic intermediate from a natural source and then adjusting it with chemical synthesis

Question 11

What was extracted from the needles of yew tree and what was it used for

Answer 11

10-deacetylbacctin III

Production of taxol

Question 12

What are the advantages of semi synthetic synthesis

Answer 12

Intermediate may be more easily extracted in higher yield than product itself

Possible to synthesise analogue of final product

Can create better oral bioavailability, improve pharmacological properties, and activity against drug resistant cancers

Question 13

What is podophyllum and what is it used for

Answer 13

Derived from the underground stem of a plant (resinous extract), it contains high concentrations of alpha and beta peltatin

Used on Warts and benign tumours- topical use

Question 14

What are the limitations of using podophyllin resin and what does it contain

Answer 14

1. Highly irritant and unpleasant
2. Cannot be used systemically
3. Lignan Glycosides is the anti-cancer agent

Question 15

What is the main product of podophyllin (its mechanism of action) and what was it marketed as initially

Answer 15

PODOPHYLLOTOXIN- prevents microtubule formation

CRUDE mixture

Question 16

What are two most important analogies semi synthesised from podophyllin and describe them including its mechanism of action

Answer 16

ETOPOSIDE: Vespid: small cell lung cancer, testicular cancer, lymphomas

TENIPOSIDE: Treatment of brain tumours, carbohydrate chemistry- inhibits topoisomerase II (prevention of DNA replication)

Question 17

What is the madagascar periwinkle and what does it treat

Answer 17

The plant that classified the vinca alkaloids and has a history of treating diseases like diabetes, skin infections

Question 18

What has a structure of dimeric indole alkloids

Answer 18

Vinca alkaloids like:

Vincristine and vinblastine (velban)

Question 19

What is the mechanism of action of vinca alkaloids

Answer 19

1. Inhibiting mitosis and by binding to tubulin, prevents cells from making spindles it needs for chromosomes as it divides

Question 20

What are the therapeutic uses of vinblastine

Answer 20

Hodgkin's disease
Lymphomas
Advanced testicular cancer
Advanced breast cancer
Kaposi's sarcoma

Question 21

What are the side effects associated with vinblastine

Answer 21

Hair loss
Nausea 
Lowered blood cell counts
Headache
Stomach pain 
Numbness, constipation
Mouth sores
Bone marrow damage

Question 22

What are the therapeutic uses of vincristine

Answer 22

Acute leukaemia
Hodgkin’s disease
Other lymphomas

Question 23

What are the therapeutic uses of vinorelbine

Answer 23

Ovarian cancer

used alongside cisplatin for non small cell lung cancers

Question 24

What is the mechanism of alkaloids

Answer 24

1. Mimics structure of monosaccharides so that it inhibits glycosides enzymes
2. Involved in a wide range of biological processes like tumour associated carbohydrate antigens
3. Has potential to inhibit synthesis of tumour associated carbohydrates

Question 25

What are natural cyanohydrins

Answer 25

Toxic constituents in a number of plants

Question 26

How do natural cyanohydrins work

Answer 26

1. Upon hydrolysis, the glycoside breaks down to afford a sugar and HCN that is toxic
2. Works as a prodrug to deliver the cyanogenic glycoside to tumours and allow HCN to be generated around tumour locality

Question 27

Define cancer chemoprevention

Answer 27

1. The administration of chemical agents that reduce or delay carcinogensis
2. Differentiation between avoiding environmental carcinogens and chemoprevention (ingesting health food or drugs from cancer chemotherapy)

Question 28

Give examples of chemopreventive agents

Answer 28

Micronutrients: vitamin A, C, E, selenium and calcium and zinc

Food additives: antioxidants

Non nutritive food molecules: carotenoids, coumarins, insoles and alkaloids

Industrial reagents: photographic developers, herbicides

Pharmaceuticals:
Retinoids, NSAIDs, antithrombotic agents

Hormones and anti-hormones:
Tamoxifen