Treatment of Cancer I & II Flashcards
What is the MOA of alkylating agents?
Alkylating Agents
- Covalently bind to/modify biological molecules
- DNA is key target
- Must be reactive–inherent, or generated by metabolism
- CCNS–but replicating cells are more sensitive
Mechlorethamine
Mechlorethamine
* A nitrogen mustard
* First alkylating agent
* Vesicant, caustic to skin, mucous membranes Intravenous only –subcutaneous causes slough, necrosis
* Often in arterial supply to tumor
* Half-life several minutes, reacts rapidly
* Primary use–Hodgkin’s lymphoma, Part of “MOPP”
Adverse Effects
* Acute–Nausea, vomiting
* Delayed–Decreased blood counts, moderate with most doses; minimum levels 10-12 days after treatment, recovery 3-6 weeks
Cyclophosphamide
Cyclophosphamide
* Oral or Intravenous
* Nitrogen mustard pro-drug; activated by host metabolism (primarily in liver)
* Widely used, including leukemias and lymphomas
Adverse effects
* Acute–Nausea and vomiting
* Delayed–bone marrow depression (moderate, dose- related)
* Alopecia
* Sterile hemorrhagic cystitis
Ifosfamide
Ifosfamide
* Analog of cyclophosphamide
* Intravenous only
* Used for Hodgkin’s and non-Hodgkin’s Lymphomas
* High-dose for bone marrow or stem cell rescue
* Component of ICE (Ifosfamide, carboplatin, etoposide)
Adverse effects
* Acute–Nausea and vomiting, urinary tract toxicity
* More severe bone marrow depression than with cyclophosphamide (Leukopenia) Peripheral neuropathies – CNS effects
* Hallucinations, coma
* May be due to chloroacetaldehyde
Melphalan
- Alkylating Agents
- Phenylalanine nitrogen mustard
- Highly reactive, chemical half-life ~50 minutes
- Oral absorption inconsistent, primarily given intravenously
- Renal excretion
- Marked myelosuppression
- Major uses–Multiple Myeloma; Myeloablative therapy
Chlorambucil
- Alkylating Agents
- Nitrogen mustard, but administered orally, once daily
- Plasma half-life ~ 1.5 hours
- Was primary drug for CLL, now used rarely
Busulfan
Busulfan
- Alkylsulfonate
- Oral administration; Intravenous for high-dose
- Prior to Imatinib, Busulfan was the key drug for CML
- Profound myelosuppression; high-dose produces pulmonary fibrosis, hepatic veno-occlusive disease
Bendamustine
- Non-Classic Alkylating Agents
- Nitrogen mustard
- Administered intravenously, Plasma half-life ~30 minutes
- Alkylates DNA, but inhibits mitotic checkpoints
- Only partial cross-resistance with other alkylating agents, suggesting additional mechanisms
- Approved for CLL and indolent B-cell non-Hodgkin’s lymphoma
- Typical alkylating agent adverse effects, including nausea and vomiting, myelosuppression and mucositis
Dacarbazine and Procarbazine
Non-Classic Alkylating AgentsDacarbazine
* Administered intravenously
* Activated by hepatic metabolism
* Severe acute nausea and vomiting; delayed myelosuppression (dose-limiting)
* Used to treat Hodgkin’s lymphoma, multiple myeloma
Procarbazine
* Oral
* Inhibits DNA, RNA, and protein synthesis; causes strand breaks
* Higher potential for secondary malignancy than with other alkylating agents (acute leukemias)
* Used for Hodgkin and non-Hodgkin lymphoma
What are the properties of antimetabolites.
Antimetabolites
- Analog of a normal component of the target cell
- Enters into a normal metabolic pathway, but then blocksthat pathway Anticancer antimetabolites
- Folate analogs
- Purine analogs
- Pyrimidine analogs
Methotrexate
Methotrexate
- Administered orally, IV, intrathecally
- Excreted in urine
- May give high dose, followed by “rescue” with folinic acid (Citrovorin, leucovorin)
- Efficacy of high dose-rescue debated
- Anti-folate effects (bone marrow, GI)
- Chronic use can produce hepatotoxicity
- Resistance–decreased drug accumulation, amplified DHFR, altered DHFR
6 Mercaptopurine and 6-Thioguanine
Anticancer Antimetabolites: Purine Analogs6-Mercaptopurine, 6-Thioguanine
- Oral administration
- Well-tolerated; bone marrow depression only at high doses
- Blocks DNA and RNA synthesis—6-MP inhibits AMP and GMP synthesis, 6-TG incorporated into RNA and DNA altering function
- Resistance from decrease in hprt activity, or increase in alkaline phosphatase
Fludarabine
Anticancer Antimetabolites: Purine AnalogsFludarabine
- Administered orally or intravenously as monophosphate
- Dephosphorylated in plasma and absorbed by cells
- Diphosphate inhibits ribonucleotide reductase
- Triphosphate inhibits DNA polymerases and ligase, incorporated into RNA and DNA
- Effective mono-or combination therapy for CLL
- Myelosuppression, nausea and vomiting
Cladribine
Anticancer Antimetabolites: Purine AnalogsCladribine (2-Chlorodeoxyadenosine, 2-CDA)
* Administered intravenously Activated by deoxycytidine kinase
- Triphosphate incorporated into DNA, causes strand breaks
- Inhibits ribonucleotide reductase
- Used for Hairy cell leukemia, CLL, and low-grade lymphomas
- Resistance if deoxycytidine kinase activity absent, if ribonucleotide reductase is upregulated, or by active efflux
- Bone marrow suppression is dose-limiting toxicity (thrombocytopenia, opportunistic infections)
Cytarabine
Anticancer Antimetabolites: Pyrimidine AnalogsCytarabine
- Intravenous or intrathecal administration
- Activated by deoxycytidine kinase– polymorphic
- Triphosphate incorporated into DNA, inhibits elongation and repair
- Used for therapy of AML; also ALL
- Far more toxic than purines: Myelosuppression, GI disturbances, stomatitis
