lec 20: Chemotherapy

DNA damage

Most classic chemotherapies lead to _____ (making them carcinogens paradoxically with toxicity and side effects)

non-localized

chemo is used to treat ______ disease ~ leukemia, lymphoma, and metastatic disease

• Troops exposed to mustard gas have profound lymphoid and myeloid suppression on autopsy

• Lymphoma is made of lymphoid cells and should also be sensitive

• Result: mustard gas derivative (nitrogen mustard) causes remission (but not complete care)

explain the discovery about mustard gas in relation to cancer

Goodman and Gilman (early 1940s)

who first administered nitrogen mustard to patients with lymphoma?

by interrupting processes or inhibiting substances necessary for cellular replication

how does chemotherapy attack cancer at the cellular level?

• Classic alkylating: cyclophosphamide, carmustine, mustard gas, etc.

• Non-classical: procarbazine, temozolomide, etc.

what are the two categories of Alkylating agents in use today?

they cause chemical changes in DNA that lead to breaks during replication

• specifically: Alkylating agents attach an alkyl group to DNA either forming a cross-link between strands or blocking access to protein-DNA interaction

what is the function of Alkylating agents?

activity of O-6-methylguanine-DNA methyltransferase (MGMT) which repairs the damage

what compromises the effectiveness of alkylating agents?

Electrolysis of the platinum electrode produced platinum compounds that killed the bacteria

how were platinum agents as a chemotherapy discovered?

they create Intrastrand crosslinks that prevent DNA repair and synthesis

common platinum agents: cisplatin and carboplatin

how do platinum agents attack cancer? what are the 2 most common types?

Sydney Farber

who was one of the first oncologists to push for the use of chemotherapy

folate (leafy greens) can worsen acute lymphoid leukemia in patient

• Folate analogues that don’t work right (anti-folate) can reverse leukemia

what was Farber’s observation?

Anti-Folate Therapy

what therapy was responsible for first leukemia remission
ever in 1948 and in 1950 similar results in breast cancer

Anti-folates block the conversion to tetrahydrofolate
- Tetrahydrofolate is required for the synthesis of thymidine and purines (adenine and guanine)

• prevents synthesis of DNA which prevents proliferation

how does anti-folate therapy work?

they work as DNA intercalating agents preventing replication

how do Anthracyclines (Antibiotic) attack cancer?

cardiac damage

what is a unique side effect of Anthracyclines?

Causes DNA strand breaks by a metal/oxygen dependent mechanism

how do Bleomycins (antibiotic) attack cancer?

Can cause pulmonary fibrosis

what is a side effect of bleomycins?

Inhibits tubulin from forming/organizing intro proper microtubule
structures
– Without proper microtubule formation, mitosis cannot progress.

how do Taxanes and Vina Alkaloids (botanicals) attack cancer?

inhibit the action of Topoisomerase I

how do Camptothecin Derivatives (botanicals) attack cancer?

They inhibit the action of Topoisomerase II

how do Epipodophyllotoxin Derivatives (botanicals) attack cancer?

it relieves supercoiling that occurs during DNA replication ahead of the replication fork

• Inhibition leads to blockage of the replication machinery
  and eventually to DNA breaks

what is the role of topoisomerase?

they mimic precursors of nucleotide bases
• Cells cannot generate the nucleotide and are therefore unable to synthesize new DNA

how do Anti-Metabolites (Nucleoside/Base Analogs) attack cancer?

a pro-drug for 5-FU which ideally makes conversion more likely to occur in tumor vs. normal tissues

• can be given orally while 5-FU is given as an IV infusion

what is Capecitabine?

VAMP (vincristine, amethopterin (methotrexate), 6-MP, and prednisone)
– Increased remission rate in leukemia to 60%

Most chemotherapy regiments today include multiple drugs. What was the first Combination Chemotherapy?

therapeutic index

Combination therapy is intended to improve the ________

disease that is missed by one agent (e.g., local radiotherapy) may be treated by another (e.g., chemotherapy)

what is spatial cooperation of combination therapy?