Lecture 44 and 45 - Anti-neoplastic Drugs

Question 1

What are the big picture categories of anti-neoplastic drugs?

Answer 1

Chemotherapies: Cytotoxics vs Targeted Therapies

Biologics: Antibodies, Ligand directed proteins, Cytokines, etc

Question 2

Which Cytotoxic Drug classes directly interact with DNA?

Answer 2

Alkylating Agents:

Platinum Derivatives –

Question 3

Mechanism of Nitrogen Mustards (alkylating agents)

Answer 3

Positive Ion formation which can interact with amine groups;

□ Chlorines have bifunctional link — Cross liking DNA between N7 of Guanine

Question 4

Clinically Important Alkylating Agents?

Answer 4

Busulfan

Melphalan, Chlorambucil, Cyclophosphamid, Ifosfamide

Question 5

Toxicities of Alkylating Agents:

Answer 5

Myelosuppression
mucositis, nausea, vomting, 
Alopecia  
 Impaired wound healing
Impaired growth in children

Sterility
Teratogenic
Carcinogenic

Question 6

Special features of certain alkylating agents ***

Question 7

Platinum Derivatives -

what is the mechanism of this class?

what are some important drugs?

Answer 7

MECHANISM: Metal forms the direct link/cross link
Bind to N7 Guanine on Single Strand

Cisplatin, Carboplatin, Oxaliplatin —

Question 8

Cisplastin –
Toxicitiy
how is this alleviated?

Answer 8

§ Renal Toxicity > Neuro; Oto > heme

□ Requires hydration to mitigate renal tox

Question 9

Anti-Tumor Antibiotics –
Mechanism
Important drugs of this class

Answer 9

Mechanism: Bind to DNA non covalently; cause damage to physical structure or alter DNA function

Important members: Bleomycin, Actinomycin D

Question 10

Bleomycine:

• Specific mechanism of dna damage
• how is it cleared?
• Toxicities (what specific tissues and why?)

Answer 10

Binds to DNA at 1 end and metal ions (iron) at other ends; can create super oxide radicals and damage DNA

Renally cleared
Cleared in certain tissues Bleomycin Hydrolase
Skin and Lung lack this enzyme;
Therefore Pulmonary and Cutaneous toxicity;
Pulmonary toxicity can occurs even years later (high o2 exposure during intubation; can be fatal)

Question 11

Actinomycin D:
- uses
Mechanism
-Toxicitiy

Answer 11

Use: Curative for a number Pediatric Cancers

Mechanism: Intercalate into DNA helix

Toxicity – Myelosuppresion, nausea, vomiting, diarrhea, mucositis, vesicant (blistering)

Question 12

Topoisomerase-Directed Acting Agents:

mechanism

Answer 12

§ Mechanism: Form ternary complex – Drug + DNA + Topo – stabilized complex and signals DNA repair and damage responses

Question 13

Topo II Directed Drugs

• classes
• specific drugs
• toxicities (key toxicity?)

Answer 13

Anthracyclines – Topo II Directed

Drugs: Doxorubicin, Daunorubicin, Epirubicin, Idarubicin

Toxicities: Myelosuppresion, Mucositis, Alopecia, vesicant, CARDIAC TOXICITY

Mitoxantrone -
Similar structure to anthracyclines
Less Cardiotoxic; less Emetogenic
Toxicities: Neutropenia, Thrombocytopenia, Alopecia

Question 14

Topo I Directed drugs:
drugs
toxicities

Answer 14

Topotecan: : N/V, myelosupression, fatigue, alopecia

Irinotecan – CPT38:
prodrug of SN38
early and late onset diarreha
Myelosuppression, alopecial, fatggue, N/V

Question 15

• Anti-Metabolites: Indirectly DNA Acting
General Mechanism:
during what stage of the cell cycle is it most active

what are some important drugs?

Answer 15

Affect DNA by affecting DNA precursors (folate, pyrimidine, purines)
Greatest Activity – S Phase active cells

Methotrexate, 5 FU, Cystosine Analogs (Azacytidine), Purine Analogs (6Mercaptopurine), Nucleosides (Fludarabine),
Pentostatin

Question 16

Methotrexate

• Mechanism
• Standard dose tox
• Rationale for giving a high dose; what can be done to mitigate toxicity in presence of high dose?

Answer 16

Inhibition of Dihydrofolate reductase (cannot reduce folate); blocking DNA and RNA precursor formation (inhibit ribonucleotide synthesis, inhibit, deoxyribonucleotides)

Standard dose
Toxicity: Myelosuppression, mucositis

High Dose + Rescue with Leucovorin
already reduced folate – rescuing normal cells, while the cancer cells are exposed to high dose of Methotrexate

Question 17

• 5 Fluorouracil
- Mechanism

• why should already reduced folates not be given?

Answer 17

Inhibits thymidine synthesis by forming covalent complex with folate and thymidylate synthase

Toxicity – Myelosuppression, Gastro

Luecovorin —
Increases formation of the enzyme + folate + 5fu complex — active state of the enzyme — enhanced toxicity

Question 18

Luecovorin:

- good and bad effects with which drugs

Answer 18

High Dose Methotrexate + Leucovorin = Good
High Dose + Rescue with Leucovorin
already reduced folate – rescuing normal cells, while the cancer cells are exposed to high dose of Methotrexate

5FU + luecovorin = bad
Increases fomration of the enzyme + folate + 5fu complex — active state of the enzyme — enhanced toxicity **

Question 19

Cytosine Analogs

• name the drugs
• Toxicity

Answer 19

Azacytidine, Deazacytidine

Tox: myelosuppression

Metabolized by cytidine deaminase

Question 20

Purine analogs

• name the drugs
• 2 mechanism

Answer 20

6-Mercaptopurine / 6-Thioguanine

Inhibition of de novo purine synthesis; Some Incorporation into DNA(6MP): dysfunction of DNA; Incorporation into RNA

Fludarabine — adenine based analogs;
○ Mechnaisms: Incorporate into DNA as false nucleotide; inhibit DNA synthetic activities

Question 21

Pentostatin

mechanism

Answer 21

NOT incorporate into DNA directly but inhiibit adenosine deaminase and therefore build-up levels of dAXPs; signal to apoptosis in T cells

Question 22

• Miscellaneous DNA Directed Agents
- name two drugs:
uses
toxicities

Answer 22

ASPARAGINASE — inhition of protein synthesis; therefore poor histones and DNA packaging
Used in a curative methods of leukemias

	• Toxicities: hypersensitivity, hyperglycemia, pancreatitis, altered clotting functions

HYDROXYUREA –

Mechanism: reversible inhibition of ribonucleotide reductase by chelation of non heme Fe

Toxicities: myelosuppression, mucosal damage. Enhanced effect in renal failure