Lecture 29 Flashcards
What are the three main forms of cancer therapy?
Surgery, radiotherapy and chemotherapy
What are the major advantages and disadvantages of chemotherapy?
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
What are the general side effects of anticancer drugs?
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
What is alopecia
When someones hair falls out
What are the principals of cell kill?
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
What is the minimal log cell kill value for cancer therapy to be used clinically?
Log 3 which is 99.9%
What occurs at 10^13 tumour cells?
Death
What occurs at 10^12 tumour cells?
Advanced disease, usually when most patients will be diagnosed
What occurs at 10^9 tumour cells?
1g of tumour present, the minimum detectable level
What occurs at 10^6 tumour cells?
1mg of tumour, not detectable and the patient enters clinical recovery
Chemotherapy must be continued well after this recovery in order to prevent relapses
What is different between the theoretical and actual relationship of number of viable tumour cells to repeated dosing?
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)
What are the reasons for cell kills being below lower than predicted in clinical practice?
Toxicity, Drug resistance (intrinsic or acquired) and the characteristics of tumour cell growth
How can toxicity of a drug lead to a difference between predicted and observed cell kills?
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
How can the characteristics of tumour cell growth lead to a difference between predicted and observed cell kills?
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)
What are cell cycle specific agents?
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)
What are cell cycle non-specific agents?
Kills both dividing and G0 cells although G0 cells are more sensitive Includes Alkylating agents (cyclophosphamide) Anthracycline antibiotics (doxorubicin) Platinum drugs
What are alkylating agents?
Cyclophosphamide, platinum drugs
Act by transferring alkyl groups to cellular constituents such as DNA, RNA and proteins
What are antimetabolites?
(Methotrexate, 5-fluorouracil)
Inhibit DNA synthesis, have similar structures to endogenous molecules required for nucleic acid synthesis
What are topoisomerase active anticancer agents?
Etoposide, induce DNA damage by inhibiting topoisomerase action
Nuclear proteins responsible for DNA’s topology
What are antimicrotubule drugs?
Vincristine, induce metaphase arrest by disrupting microtubules and mitotic spindle
What are the hormonal agents used in anticancer therapy?
Tamoxifen which is an antioestrogen for breast cancer and antiandrogens for prostate cancer
These drugs block receptors and change the hormonal environment
What are the targeted therapies used in anticancer therapy?
Transtuzumab (Herceptin), these compunds target specific molecules involved in cancer progression
What are the mechanisms of chemotherapy resistance developed in cancer cells?
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
How does combination chemotherapy overcome resistance?
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
