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Cell Cycle
- M - chromosomes segregated and divided (cell divides)
- G1 - components for DNA replication synthesized
- S - replication of DNA
- G2 - cell prepares to divide
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transferring alkyl groups onto DNA
nucleophil on DNA displaces leaving group on the alkylating agent
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Alkylating agent classes
- Nitrogen mustards
- ethyleneimine
- alkyl sulfonates
- nitrosoureas
- triazenes
- platinum coordination complexes
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Nitrogen mustards agents
- mechlorethamine
- cyclophosphamide
- ifosfamide
- melphalan
- chlorambucil
- bendamustine
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Ethyleneimine agents
thiotepa
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Alkyl sufonates agents
busulfan
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-
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platinum coordination complexes
- carboplatin
- cisplatin
- oxaliplatin
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cyclophosphamide route of admin
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ifosfamide route of admin
iv
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chlorambucil route of admin
- po
- continuously on chronic basis
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bendamustine route of admin
iv
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chemical structure of nitrogen mustards
- Bis(chloroethyl) groups
- rest of mlcl determines physical properties and affects transport, distribution, and reactivity
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nitrogen mustard activation
- non-enzymatic
- to aziridinium intermediate
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historical use of mechlorethamine
- MOPP regimen for hodgkin's lymphoma
- Stanford V
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what has mechlorethamine been replaced by and why?
- cyclophosphamide
- less secondary malignancies and infertility
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uses of mechlorethamine
- NHL (non-hodgkins)
- intracavitary injection in metastatic tumors
- cutaneous T-cell lymphoma
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mechlorethamin AEs
- myelosuppresion (dose-limiting)
- emtogenicity (very high)
- infertility
- vesicant
- secondary malignancy
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how to avoid extravasation with mechlorethamine
use sodium thiosulfate
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mechlorethamine clinical pearls
- use within 1 hr of reconsitution (fast hydrolysis and demethylation in solution)
- slow IV push
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melphalan uses
- multipe myeloma
- autologous stem cell transplatn in elderly pts
- unresectable epithelia ovarian cancer
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if melphalan given before a autologous transplant?
impairs ability to harvest adequate quantity of stem cells
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melphalan AEs
- myelosupression
- infertility
- secondary malignancy
- less common:
- pulmonary fibrosis
- interstitial pneumonitis
- rahses
- cardiac arrest
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melphalan emetogenicity
very low
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mechlorethamine emetogenicity
very high
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mephalan clinical pearls
- take tabs on empty stomach
- store tabs in fridge
- use IV solution within 60 min of reconsititution
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primary use of chorlambucil
chronic lymphocytic leukemia
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chlorambucil uncommon uses
- hodgkin's lymphoma
- non hodgkin's lymphoma
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chlorambucil AEs
- infertility
- secondary malignancies
- less common:
- seizures (with pulsing dose)
- tremor, muscle twitching, agitation, confusion
- ataxia
- pulmonary fibrosis
- hepatotoxicity
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chlorambucil emtogenicity
very low
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chlorambucil monitory
weekly CBCs
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chlorambucil clinical pearls
- take on empty stomach
- keep in fridge
- mildest treatment with least toxicities
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chlorambucil brand name
Leukeran
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melphalan brand name
Alkeran
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Leukeran generic name
chlorambucil
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Alkeran generic name
melphalan
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most used nitrogen mustard
cyclophosphamide
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cyclophosphamide use
all types of cancers (breast, CLL, NHL, acute lymphoblastic leukemia, multiple myeloma)
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cyclophosphamide AEs
- myelosuppresion
- alopecia
- infertility
- N/V
- mucositis
- hemorrhagic cystitis
- Less common:
- SIADH
- heart failure
- secondary malignancies (AML, bladder cancer)
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cyclophosphamide emetogenicity
dose-dependent and route dependent
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how to minimize risk of hemorrhagic cystis with use of cylcophosphamide
- MESNA
- forced diuresis
- fluid intake >/2 2 L per day
- take in morning to dec inc in nighttime bladder exposure to acrolein
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what metabolite causes hemorrhagic cystitis with use of cylcophosphamide?
acrolein
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MESNA MOA
- circulates in blood as inactive oxidized form (dimesna)
- excrete into the urine and partially reduced to monomeric form
- free sulfhydryl group inactivates acrolein (Michael rxn)
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ifosfamide chemical structure
- isomer of cylcophosphamide
- slower metabolism --> more chloracetaldehyde (encephalopathy)
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ifosfamide dosage form
iv inpatient
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ifosfamide toxic metabolite
- chloracetaldehyde
- causing encephalopathy
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ifosfamide and MESNA
mandatory
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ifosfamide uses
- testicular cancer
- sarcoma
- non-hodgkins lymphoma
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ifosfamide AEs
- hemorrhagic cyctitis
- encephalophathy
- myelosuppresion
- N/V
- infertility
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ifosfamide emetogenicity
moderate
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risk factors for encephalopathy
- hypoalbuminemia
- renal dsfx
- pelvic mass
- hx of ifosfamide-induced encephalopathy
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sx's of encephalopathy
- confusion
- somnolence
- coma
- delirium
- confusion
- hallucinations
- stupor
- personality changes
- twitching
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sometimes given to treat ifosfamide-induced encephalopathy
methylene blue
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bendamustine chemical properties
- water-soluble
- amphoteric
- bifunctional compound
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bendamustine chemical structure
- not a pro-drug
- benzimidazole ring has purine analog activity
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bendamustine cross resistance with other alkylators
- not repaired by typical alkyltransferase enzymes
- little cross-resistance
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bendamustine uses
- common: NHL, CLL
- other: mantle cell lymphoma, multiple myeloma
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bendamustine AEs
- very well tolerated
- myelosuppresion
- skin reactions
- infusion reactions
- N/V
- fatigue
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bendamustine metabolism
CYP 1A2
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Bendamustine dose adjustment
- avoid in CrCl <40 ml/min
- avoid in moderate-severe hepatic impairment
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bendamustine drug-drug interaction
- inhibitors of CYP 1A2: cipro, fluvoxamine
- inducers of CYP 1A2: omeprazole, smoking
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busulfan chemical workings
- bifunctional alkylating agent
- SN2 rxn
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busulfan especially toxic to:
- myeloid cells
- hematopoietic stem cells
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historic use of busulfan
chronic oral therapy for chronic myelogenous leukemia
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current use of busulfan
allogenic stem cell transplantation combined with cylophosphamide or fludarabine
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busulfan route of admin and why
- iv preferred over oral
- dec in risk hepatic veno-occlusive disease (VOD)/sinosoidal obstruction syndrome (SOD)
- avoid variation in bioavailability
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busulfan PK
- distribution into CSF
- hepatic metabolism (gluthione conjugation and CYP 3A4
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busulfan drug interactions
- APAP (glutathione depletion
- metronidazole
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busulfan AEs
- seizures
- pulmonary fibrosis
- SOS/VOD
- myelosuppression
- secondary malignancies
- N/V
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busulfan seizure prophylaxis
- phenytoin
- levetiracetam
- benzodiazepine
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busulfan emetogenicity
moderate
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