Cancer Chemotherapy Flashcards
Define cancer, tumour and metastasis.
Cancer refers to a disease where cells divide abnormally without control and spread to other parts of the body (metastasis). This typically results in tumor growth but can affect blood. Tumours may be solid or liquid.
Describe the 4 major types of cancer.
- Carcinoma - tumors derived from skin or tissue linings, such as skin, stomach, prostate, pancreas, lung, liver, etc. Most common type of cancer/cause of tumour.
- Sarcoma - tumours originating from connective tissue like cartilage, bones, fat and nerves. (-sarcoma such as liposarcoma)
- Blastoma - tumours from embryonic or immature cells. More common in childeren. (-blastoma such as retinoblastoma)
- Lymphoma/Leukaemia - from blood forming cells in bone marrow or lymph nodes. No tumours are formed in leukaemia and represents 30% of childhood cancers.
Describe the causes of cancer.
- Environment/Lifestyle - smoking, high fat diet.
- Radiation - UV, x-rays.
- Genetic factors - predisposition for breast cancer.
- Viral/Bacterial - viruses can mutate DNA to form cancer cells in cervical and gastric cancer.
- Chemicals - carcinogens, asbestos.
- Others - age, supressed immune system, hormones.
What are the three main ways to treat cancer and other new methods.
Sugery, hormone and chemotherapy. Gene therapy is also emerging.
Outline ancient approaches to cancer treatment and radiotherapy.
Tumours have been recognised by many civilisations but medicine was very limited. Surgery was explored but success was difficult due to infection and tumours often returned. Chemotherapy was attempted but had very limited success.
In the late 19th century x-rays were discovered and used to treat tumours by generating radicals. This become much more useful when more powerful x-ray sources were developed and are now used as a stand alone cancer treatment and in conjunction with chemo and surgery.
Describe the origins of hormone therapy and chemotherapy approaches to treating cancer.
Hormone therapy was developed in the 30s/40s and are used to treat tumours which are dependant on specific hormones. Key drugs include tamoxifen and abiraterone.
Chemotherapy came from chemical warfare where nitrogen mustards (RN(CH2CH2Cl)2) were developed. They work by cross-linking and alkylating DNA. This found very good results, especially for patients not responding to radiotherapy. Another cross-linker cis-platin improved testicular cancer cure rates from 10 to 85%.
Describe how DNA synthesis can be inhibited to treat cancer aside from cross linking and mimicing DNA bases.
It has been shown that folic acid is essential for DNA synthesis and therefore required for tumour growth. A structural analouge of folic acid is used to treat leukaemia, breast and lung cancer.
Describe the discovery process of natural product chemotherapy, giving the two major discoveries, and new chemotherapy approaches.
Random screening of natural products was caried out on in vitro cancer cells. Two major discoveries were DNA intercolators - major and minor groove binders inhibiting DNA replication, and mitosis/tubulin interference.
New approaches include methods to direct therapies to only the tumour area, such as antibody prodrugs. These all have the aim of reducing side effects.
Define agonist and antagonist.
Describe the structure of natural steroids testosterone and estradiol and how synthetic steroids with similar structures can be used to treat cancer.
Agonist - biological mimic which occupies active sites and triggers a desired biological effect.
Antagonist - blocks the active site of a natural substrate to stop enzymes function.
Testosterone and estradiol have a 4 ring structure with an oxygen functionality at both ends. They differ by aromaticity and methyl groups. Antagonist of testosterone, abiraterone, has a pyridine ring replacing one OH group and different oxygen functionality. It is used to treat prostate cancer. Agonist of estrogen is used as an oral contraceptive.
The structure of estradiol is shown along with an agonist and antagonist. Which compound belongs to each class? Explain why.
Stilboestrol has a similar carbon framework and oxygen functionalilty to estradiol so it is an agonist.
Tamoxifen looks similar but appears like the opposite alkene isomer to estradiol. This makes it an antagonist.
Describe the mode of action of tamoxifen.
Estrogen binds to a receptor which binds to DNA with a coactivator, activating the related genes. As tamoxifen is an antagonist, it binds to the same receptor but cannot bind to the coactivator. This stops the genes activity and the key protein for activity.
Describe the structure of DNA, highlighting key targets for drugs.
The basic structure of a DNA strand is phosphate units linking deoxyribose units. One of 4 bases are linked to the sugar groups. The bases are either based on a pyrimidine (6 membered ring with 2 nitrogens at 1 and 3) ring (C/T) or purine (same as pyrimidine with attached 5 membered ring with 2 nitrogens) ring (A/G).
There are complimentary hydrgoen bonds between bases and they are double stranded. All bases are nucleophilic via N and O atoms.
Describe the mode of action of nitrogen mustards and their general structure.
Nitrogen mustards are amines with two CH2CH2Cl groups and an alkyl group. The central N undergos an intramolecular substitution to eliminate the chlorine and form a three-membered ring. This is highly electrophilic and the DNA nucleophiles react with it. This occurs on both ends of the molecule and cross-links the DNA.
The most nucleophilic sites are N7 and O6 on guanine.
How can the nitrogen mustards be modified to enhance drug properties?
The alkyl group can be replaced with drugs that increase uptake into cancer cells. Adding an Uracil group was thought to be uptaken into rapidally dividing cells as it is required in DNA biosynthesis. However it still has toxic side effects to bone marrow and causes nausea.
How were prodrugs investigated to be used with nitrogen mustards?
A cyclophosphamide was investigated as when metabolised it has an additional OH group added. This increases the reactivity from an effectively inactive form to an active form. However a toxic side product, acrolein, is formed. This was addressed by co-administering sulfur compounds to form soluble species.
Draw a diagram to illustrate the division of a cell nucleus and the action of drugs on this target.
As the chromosomes divide, a mitotic spindle is generated which links the two daughter cells. The spindle is composed of microtubule polymers, formed of tubulin proteins. Tubulin can be bound to to prevent spindle formation (vinblastine and vincristine) or spindles can be stabilised to prevent dissasembly (taxol). Taxol is particularly effective against against solid tumours however it has challenges from its origin (pacific yew tree).
