Lecture 44 and 45 - Anti-neoplastic Drugs Flashcards
What are the big picture categories of anti-neoplastic drugs?
Chemotherapies: Cytotoxics vs Targeted Therapies
Biologics: Antibodies, Ligand directed proteins, Cytokines, etc
Which Cytotoxic Drug classes directly interact with DNA?
Alkylating Agents:
Platinum Derivatives –
Mechanism of Nitrogen Mustards (alkylating agents)
Positive Ion formation which can interact with amine groups;
□ Chlorines have bifunctional link — Cross liking DNA between N7 of Guanine
Clinically Important Alkylating Agents?
Busulfan
Melphalan, Chlorambucil, Cyclophosphamid, Ifosfamide
Toxicities of Alkylating Agents:
Myelosuppression mucositis, nausea, vomting, Alopecia Impaired wound healing Impaired growth in children
Sterility
Teratogenic
Carcinogenic
Special features of certain alkylating agents ***
Platinum Derivatives -
what is the mechanism of this class?
what are some important drugs?
MECHANISM: Metal forms the direct link/cross link
Bind to N7 Guanine on Single Strand
Cisplatin, Carboplatin, Oxaliplatin —
Cisplastin –
Toxicitiy
how is this alleviated?
§ Renal Toxicity > Neuro; Oto > heme
□ Requires hydration to mitigate renal tox
Anti-Tumor Antibiotics –
Mechanism
Important drugs of this class
Mechanism: Bind to DNA non covalently; cause damage to physical structure or alter DNA function
Important members: Bleomycin, Actinomycin D
Bleomycine:
- Specific mechanism of dna damage
- how is it cleared?
- Toxicities (what specific tissues and why?)
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)
Actinomycin D:
- uses
Mechanism
-Toxicitiy
Use: Curative for a number Pediatric Cancers
Mechanism: Intercalate into DNA helix
Toxicity – Myelosuppresion, nausea, vomiting, diarrhea, mucositis, vesicant (blistering)
Topoisomerase-Directed Acting Agents:
mechanism
§ Mechanism: Form ternary complex – Drug + DNA + Topo – stabilized complex and signals DNA repair and damage responses
Topo II Directed Drugs
- classes
- specific drugs
- toxicities (key toxicity?)
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
Topo I Directed drugs:
drugs
toxicities
Topotecan: : N/V, myelosupression, fatigue, alopecia
Irinotecan – CPT38:
prodrug of SN38
early and late onset diarreha
Myelosuppression, alopecial, fatggue, N/V
• Anti-Metabolites: Indirectly DNA Acting
General Mechanism:
during what stage of the cell cycle is it most active
what are some important drugs?
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
Methotrexate
- Mechanism
- Standard dose tox
- Rationale for giving a high dose; what can be done to mitigate toxicity in presence of high dose?
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
• 5 Fluorouracil
- Mechanism
- why should already reduced folates not be given?
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
Luecovorin:
- good and bad effects with which drugs
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 **
Cytosine Analogs
- name the drugs
- Toxicity
Azacytidine, Deazacytidine
Tox: myelosuppression
Metabolized by cytidine deaminase
Purine analogs
- name the drugs
- 2 mechanism
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
Pentostatin
mechanism
NOT incorporate into DNA directly but inhiibit adenosine deaminase and therefore build-up levels of dAXPs; signal to apoptosis in T cells
• Miscellaneous DNA Directed Agents
- name two drugs:
uses
toxicities
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
