Lecture 29

Question 1

What are the three main forms of cancer therapy?

Answer 1

Surgery, radiotherapy and chemotherapy

Question 2

What are the major advantages and disadvantages of chemotherapy?

Answer 2

Has the advantage of being able to eliminate micro-metastases, removed from the site of origin (not seen in surgical or radiotherapy treatments)
Has the disadvantage of lacking selective toxicity with compounds commonly being cytotoxic to normal cells, particularly those with rapid proliferation

Question 3

What are the general side effects of anticancer drugs?

Answer 3

Suppression of the bone marrow and immune system
Many cause nausea and vomiting
Oral and GI ulceration
Alopecia
Can target the germ cells to cause sterility and teratogenicity
Some evidence that long term use of some of these compounds like alkylating agents can be carcinogenic

Question 4

What is alopecia

Answer 4

When someones hair falls out

Question 5

What are the principals of cell kill?

Answer 5

Anti-Cancer drugs kill according to first order kinetics (a given dose will kill a constant fraction of the tumour cells)
For most drugs a relationship of increasing the drug dose will result in a greater cell kill

Question 6

What is the minimal log cell kill value for cancer therapy to be used clinically?

Answer 6

Log 3 which is 99.9%

Question 7

What occurs at 10^13 tumour cells?

Answer 7

Death

Question 8

What occurs at 10^12 tumour cells?

Answer 8

Advanced disease, usually when most patients will be diagnosed

Question 9

What occurs at 10^9 tumour cells?

Answer 9

1g of tumour present, the minimum detectable level

Question 10

What occurs at 10^6 tumour cells?

Answer 10

1mg of tumour, not detectable and the patient enters clinical recovery
Chemotherapy must be continued well after this recovery in order to prevent relapses

Question 11

What is different between the theoretical and actual relationship of number of viable tumour cells to repeated dosing?

Answer 11

The theoretical relationship shows the number of viable tumour cells decreasing linearly while in reality the relationship consists of a decrease with some increases (zig zag shape)

Question 12

What are the reasons for cell kills being below lower than predicted in clinical practice?

Answer 12

Toxicity, Drug resistance (intrinsic or acquired) and the characteristics of tumour cell growth

Question 13

How can toxicity of a drug lead to a difference between predicted and observed cell kills?

Answer 13

Toxicity can suppress the bone marrow to the point where treatment may have to be delayed to allow blood cell count to recover, so tumour cell numbers will also recover

Question 14

How can the characteristics of tumour cell growth lead to a difference between predicted and observed cell kills?

Answer 14

The constant log cell kill is obtained with biochemically homogenous cells while in reality a tumour has a mixture of 2 main cell types (actively dividing and G0 quiescent cells, most are the latter drug-resistant type)

Question 15

What are cell cycle specific agents?

Answer 15

Agents that act a certain phase of the cell cycle, G0 cells are unaffected
Includes:
Antimetabolites (methotrexate, 5-fluorouracil)
Antimicrotubules (vinka alkaloids)
Podophyllin alkaloids (etopside)

Question 16

What are cell cycle non-specific agents?

Answer 16

Kills both dividing and G0 cells although G0 cells are more sensitive
Includes
Alkylating agents (cyclophosphamide)
Anthracycline antibiotics (doxorubicin)
Platinum drugs

Question 17

What are alkylating agents?

Answer 17

Cyclophosphamide, platinum drugs

Act by transferring alkyl groups to cellular constituents such as DNA, RNA and proteins

Question 18

What are antimetabolites?

Answer 18

(Methotrexate, 5-fluorouracil)

Inhibit DNA synthesis, have similar structures to endogenous molecules required for nucleic acid synthesis

Question 19

What are topoisomerase active anticancer agents?

Answer 19

Etoposide, induce DNA damage by inhibiting topoisomerase action
Nuclear proteins responsible for DNA’s topology

Question 20

What are antimicrotubule drugs?

Answer 20

Vincristine, induce metaphase arrest by disrupting microtubules and mitotic spindle

Question 21

What are the hormonal agents used in anticancer therapy?

Answer 21

Tamoxifen which is an antioestrogen for breast cancer and antiandrogens for prostate cancer
These drugs block receptors and change the hormonal environment

Question 22

What are the targeted therapies used in anticancer therapy?

Answer 22

Transtuzumab (Herceptin), these compunds target specific molecules involved in cancer progression

Question 23

What are the mechanisms of chemotherapy resistance developed in cancer cells?

Answer 23

Enhanced expression or alteration of target
Increased production of glutathionine which can inactivate drugs like alkylating agens to aid in elimination
Increase repair capacity of DNA damage
Increase expression of P-glycoprotein efflux pump which can lead to multidrug resistance

Question 24

How does combination chemotherapy overcome resistance?

Answer 24

Combine only agents which are active alone against the tumour
Combine agents with differing mechanisms of action
Combine with different toxicity profiles if possible
Use the maximum tolerated dose at the outset- initial aggressive therapy