Malignant Disease and Immunosuppression

Question 1

Antimetabolites (3)

Answer 1

6-Mercaptopurine, 5-fluorouracil, Methotrexate

Anti metabolites are structurally similar to either purine or pyrimidine bases and are able to prevent the normal base pairs becoming incorporated into DNA during the S phase of the cell cycle, stopping normal development and division.

6-Mercaptopurine competes with purines.
5-FU is a pyrimidine analogue
Methotrexate is both and antimetabolite and an antifolate drug. In cancer (different mechanism to in RA), methotrexate competitively inhibits dihydrofolate reductase (DHFR). This prevents the formation of folic acid which is needed for de novo synthesis of the nucleoside thymidine which is necessary for DNA synthesis. Folate is also essential for purine and pyrimidine base synthesis so this will also be inhibited. Methotrexate therefore inhibits synthesis of DNA, RNA, proteins and thimidylates.

Question 2

Vinca-Alkaloids: MT inhibitors (2)

Answer 2

Vincristine, Vinblastine

Vincristine is a chemotherapy agent (spindle toxin) that works by binding to the tubular protein which stops cells from separating their chromosomes during metaphase which forces the cell to undergo apoptosis. As this affects all rapidly dividing cells, it also inhibits intestinal epithelium and bone marrow as well as cancer cells.

ADRs include change in sensation, hair loss, constipation, difficulty walking, headaches, neuropathic pain, lung damage and low white cell count.

Vinblastine works in the same manner although ADRs for Vinblastine are hair loss, loss of white blood cells and platelets, GI problems, hypertension, excess sweating, depression, muscle cramps, headaches and vertigo

Question 3

Taxanes: MT Inhibitors (1)

Answer 3

Paclitaxel

Paclitaxel targets tubulin leading to defects in mitotic spindle assembly, chromosome segregation and cell division. Paclitaxel stabilises the microtubule polymer, protecting it from disassembly, meaning chromosomes cannot achieve a metaphase assembly, blocking progression of mitosis. Prolonged activation of the mitotic checkpoint triggers apoptosis of the cell (or reversion to the G-phase of he cell cycle without cell division).

ADRs include hair loss, muscle and joint pain and diarrhoea. It also increases risk of infection and use during pregnancy often results in problems with the infant.

Question 4

Alkylating Related Antineoplastic drugs (1)

Answer 4

Cisplatin (Platinum)

Cisplatin reacts in vivo, binding to and causing cross linking of DNA which ultimately triggers apoptosis.
N.B. Cisplatin is frequently designated as an alkylating agent, it it has no alkyl group so cannot carry out alkylating reactions. Therefore it is classed as an alkylating-like agent.

Question 5

Anti-proliferation Immunosuppressants (3)

Answer 5

Azathioprine, Cyclophosphamide and Mycophenolate Mofetil (MMF)

Azothioprine - an immunosuppressant used in organ transplantation and autoimmune disease. It is a purine analogue that acts as a prodrug for mercaptopurine which inhibits enzymes required for DNA synthesis. Thus it most strongly affects proliferating cells such as T and B cells of the immune system. It’s main ADR is bone marrow suppression which can be life threatening.

Cyclophosphamide - an alkylating agent that attaches to guanine bases, this interfering with DNA replication by forming intrastrand and inter strand crosslinks. It is used to treat cancers, autoimmune disorders and AL amyloidosis. It is a prodrug that is metabolised by the CYP450 enzymes to its active metabolite. ADRs are severe and include acute myeloid leukaemia, bladder cancer, haemorrhaging cystitis and permanent infertility. (In autoimmune disease it is often substituted for less toxic options such as azathioprine or methotrexate after an acute event).

Mycophenolate Mofetil is as immunosuppressant used to prevent rejection in organ transplantation by inhibiting an enzyme needed for T and B cell growth. It is also being increasingly used as a steroid soaring treatment in autoimmune disease. ADRs include diarrhoea, nausea, vomiting, joint pain, increased risk of infection, leukopenia, anaemia and more rarely oesophagitis, gastritis, GI haemorrhage.

Question 6

Calcineurin Inhibitors (2)

Answer 6

Cyclosporin, Tacrolimus

Cyclosporine is an immunosuppressive drug used in organ transplantation to prevent rejection. It reduces the activity of the immune system by interfering with the activity and growth of T cells. ADRs include gingival hyperplasia, convulsions, peptic ulcers, pancreatitis, fever, vomiting, vomiting, confusion, hyoercholesterolaemia, hypertension, dyspnoea, Hyperkalaemia, nephrotoxicity and hepatotoxicity.

Tacrolimus is an immunosuppressive drug used mainly after allogeneic organ transplant to lower the risk of organ rejection. It works by inhibiting IL-2 which promotes development and proliferation of T cells which are vital to the adaptive immune response.

Question 7

Anthracycline Antibiotics (2)

Answer 7

Doxorubicin, Daunoribicin

Anthracycline antibiotic drugs are used in cancer chemotherapy. They are amongst the most effective anti-cancer agents and are effective against more types of cancer than any other class of chemotherapy agent.
Main ADR is cardiotoxicity, but also vomiting.

They work by:

(1) Inhibiting DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand thus preventing replication of rapidly dividing cancer cells.
(2) They block the topoisomerise II enzyme which blocks transcription and replication.
(3) They induce iron-mediated generation of free oxygen radicals that damage DNA, proteins and cell membranes.
(4) They induce histone eviction from chromatin that deregulates DNA damage response.