Alkylators Flashcards
What’s the general mechanism of resistance to non-traditional alkylators?
- MGMT/AGT
- incompetent mismatch repair (MMR)
What is the site of attack for non-traditional alkylators?
O-6 guanine
What is the site of attack for traditional alkylators?
N-7 guanine
Which alkylators require active transport?
- Melphalan = leucine transporter
- metchlorthamine = choline transporter
- streptozotocin - GLUT2
Which alkylators required metabolic activation?
- Ifosfamide
- cyclophosphamide
- dacarbazine
- procarbazine
Which alkylators will cross the BBB?
- CCNU
- temozolomide
- dacarbazine (minimal)
- procarbazine
Which alkylators rely on incompetent BER (base excision repair)?
the classic alkylators: metchlorthamine, melphalan, cyclophosphamide, ifosfamide, chlorambucil
What can be given with mechlorethamine extravasation?
sodium thiosulfate.
Mechlorethamine is a vesicant
What’s the DLT for conventional mechlorethamine containing protocol?
DLT = GI and bone marrow suppression
What’s the typical dose for mechlorethamine?
in these protocols is reported as 3 mg/m2
IV on days 0 and 7 of a 21- or 28-day cycle
What are some dosing schedules for melphalan?
- dogs and cats: 0.1 mg/kg daily for 10 to 14 days should be reduced
to 0.05 mg/kg daily - dogs: 7 mg/m2 daily for 5 days
every 3 weeks or 2 mg/m2 daily for 10 days with a 10-day off cycle
What’s the primary toxicity of melphalan?
myelosuppression
What’s the major DLT for cyclophosphamide?
Neutropenia
What’s the DLT for ifosfamide?
myelosuppression, but nephrotoxicity and damage to the bladder epithelium are not uncommon
What supportive therapy should be given concurrently with ifosfamide?
MESNA
What’s the DLT for chlorambucil?
myelosuppression
(granulocyte and thrombocyte)
What’s the major DLT for CCNU?
myelosuppression with acute neutropenia, cumulative thrombocytopenia
dogs - elevation in ALT
What are some dosing schedules for chlorambucil?
Dogs: 4mg/m2 PO daily
cats: 2mg EOD or M-W-F; also 20mg/m2 oral bolus once every 2 weeks
What are some unique toxicities of streptozotocin?
can induce diabetes mellitus and has no significant bone marrow toxicity
What’s the major DLT for dacarbazine?
GI toxicity
occasionally has sever myelosuppression
What’s the dose for dacarbazine single agent?
800-1000mg/m2 IV every 3 weeks
What’s dacarbazine mostly used for?
- single agent or in combination with doxorubicin or CCNU for LSA.
- also used in hemangiosarcoma with doxorubicin with or without vincristine
What’s the dose of dacarbazine in combination therapy?
600-800mg/m2 IV or spread over several days (200mg/m2 IV x 5 days)
Which alkylator is not recommended for cats?
temozolomide
- causes pleural and pericardial effusion
What’s the usual indication of temozolomide?
glioma
melanoma
