WK3 - Chemotherapy - Antimetabolites and anti-mitotic

What are microtubules and what do they do?

Microtubules are protein structures made of alpha and beta tubulin dimers. They provide structural support, move organelles inside cells, and form the mitotic spindle for chromosome separation during mitosis.

What are the two phases of microtubule assembly at the MTOC?

Nucleation (tubulin dimers come together to start the microtubule) and Elongation (more dimers are added to grow the microtubule).

How do vinca alkaloids (vincristine, vinblastine) work?

They bind to free alpha-beta tubulin dimers and prevent them from assembling into microtubules. The mitotic spindle falls apart. Cells cannot divide.

How do taxanes (paclitaxel, docetaxel) work?

They stabilise microtubules and prevent them from disassembling. This locks the mitotic spindle in place. Cancer cells try to divide anyway and die from catastrophic mitosis.

What is the difference between vinca alkaloids and taxanes?

Vinca alkaloids = destabilise microtubules (prevent assembly). Taxanes = stabilise microtubules (prevent disassembly). Both block mitosis but through opposite mechanisms.

What are the main toxicities of vincristine and vinblastine?

Vincristine = peripheral neuropathy (nerve damage). Vinblastine = bone marrow suppression.

What are the two main resistance mechanisms for anti-mitotic drugs?

1) Overexpression of P-glycoprotein (P-gp) – pumps drug out of the cell. 2) Mutations in tubulin genes – reduces drug binding.

Why do cancer cells die from microtubule inhibitors while normal cells may only arrest?

Normal cells have a functional M checkpoint – they arrest in mitosis and survive. Cancer cells often lack this checkpoint – they try to divide anyway and die from catastrophic mitosis.

What is the basic idea behind antimetabolites?

They are toxic analogues of essential precursors for DNA and RNA. They trick the cell into using them instead of the real thing, inhibiting enzymes or disrupting macromolecule function.

What is the mechanism of 5-fluorouracil (5-FU)?

5-FU is converted to 5-FdUMP. This binds to thymidylate synthase plus methylene-tetrahydrofolate, forming a "frozen transition state" that permanently blocks the enzyme. No T for DNA → no replication → cell death.

What is a "frozen transition state" in 5-FU mechanism?

A stable complex formed between 5-FdUMP, thymidylate synthase, and methylene-tetrahydrofolate. The enzyme is permanently blocked and cannot make thymidine for DNA.

What other mechanism does 5-FU use to kill cells?

5-FU is also incorporated into RNA and DNA instead of normal bases, disrupting their normal function.

What is the mechanism of methotrexate?

Methotrexate is a folate mimic. It competitively inhibits dihydrofolate reductase (DHFR), preventing conversion of dihydrofolate to tetrahydrofolate. No tetrahydrofolate → no thymine or purines → no DNA synthesis.

What is the target enzyme of methotrexate?

Dihydrofolate reductase (DHFR).

What is the target enzyme of 5-fluorouracil?

Thymidylate synthase (after conversion to 5-FdUMP).

What is the difference between methotrexate and 5-FU?

Methotrexate inhibits DHFR (blocks folate recycling, affecting both purines and pyrimidines). 5-FU inhibits thymidylate synthase (specifically blocks thymidine production).

What are purine antimetabolites and give examples?

They are analogues of purines (adenine, guanine). Examples: 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). Used for acute lymphocytic leukaemia.

How do purine antimetabolites work?

1) They inhibit enzymes in purine synthesis. 2) They get incorporated into DNA, disrupting base-pairing and replication.

What are the main toxicities of antimetabolites (5-FU, methotrexate, 6-MP)?

Bone marrow depression (all affect rapidly dividing cells), nausea, vomiting.

Which drugs are used for acute lymphocytic leukaemia (ALL)?

Methotrexate and 6-mercaptopurine (6-MP).

Complete the sentence: "Vinca alkaloids bind to free ___________ dimers and prevent ___________."

tubulin / assembly

Complete the sentence: "Taxanes prevent microtubule ___________ , locking the mitotic spindle in place."

disassembly

Complete the sentence: "5-FU is converted to ___________ , which inhibits ___________ synthase."

5-FdUMP / thymidylate

What does MTOC stand for and what happens there?

Microtubule Organising Centre. Microtubules form here in two phases: nucleation then elongation.

What is the difference in toxicity between vincristine and vinblastine?

Vincristine causes more peripheral neuropathy. Vinblastine causes more bone marrow suppression.

What cancer is 6-mercaptopurine mainly used for?

Acute lymphocytic leukaemia (ALL).