-
Alkylators - MoA
- form covalent bonds with cellular structures (proteins, DNA, RNA)
- N7 position guanine on DNA
- more toxic in cells with DNA repair deficient
- cell cycle NON-specific
-
Alkylators - Adverse Effects
- BM suppression
- Vesicant
- Hemorrhagic cystitis
- Secondary malignancy
-
Alkylators - Resistance
- MDR protein increase
- Intracellular thiol increase
- Enzymatic inhibition increase
- DNA repair mechanism increase
-
Nitrogen mustard
- Alkylator
- extreme vesicant
-
Chlorambucil
- Alkylator
- used for slow progressive malignancies
-
-
Cyclophosphamide
- Alkylator
- cause Hemorrhagic cystitis (give MESNA)
-
Ifosfamide
- Alkylator
- cause Hemorrhagic cystitis (give MESNA)
-
Nitrosourea
- Alkylator
- cross BBB (fat soluble)prolonged BM suppression
-
Busulfan
- Alkylator
- old CML drugs (replaced Gleevac)
- significant pulmonary toxicity (interstitial fibrosis)
-
Dacarbazine
- Alkylator
- Use: metastatic melanoma
-
Procarbazine
- Alkylator
- antabuse/disulfiram effect (avoid alcohol)
-
Temozolamide
- Alkylator
- cross BBB
- Use: Glioma
-
What is MESNA used for?
(Mercapto Ethane Sulfonate sodium)
- prevent hemorrhagic cystitis caused by alkylators that has a toxic intermediate (Acrolein)
- - Ifosfamide & Cyclophosphamide
-
Anti-Metabolites - MoA
- resembles normal molecules but inhibits normal cellular process
- cell cycle specific
-
Methotrexate - MoA
(anti-metabolite)
- inhibits Dihydrofolate reductase (DHFR)multiple cancer use
- intrathecal use for brain tumor (stays in CSF by BBB)
- 3rd spacing effect
-
Methotrexate - Adverse Effects
(anti-metabolites)
- BM suppression
- skin rash
- mucositis
- Hepatotoxicity
- Pulmonary toxicity
- (just think of organs that replicates really fast)
-
Methotrexate - Resistance
(anti-metabolites)
- increase DHFR
- decrease DHFR affinity
- decrease uptake into cell
- decrease polyglutamate (needed to trap MTX in cell)
-
Pemetrexed
Ralititrexed
anti-folate
-
what do you use to control Methotrexate toxicity
- Folate resucue (Leucovorin)
- when MTX killed all the rapidly dividing cells, we then use Leucovorin to help and safe all the normal cells from further damage
-
5-Fluorouracil (anti-pyrimidines)
Capecitabine (pro-drug of 5-FU)
- MoA:
- - inhibits Thymidylate synthetase
- - incorporated into RNA (5F-dUMP)
- - activity enhanced by folinic acid
- AE: BM suppression, Mucositis, Sun sensitivity
- Resistance:
- - decrease PRPP - allopurinol (activates 5-FU)
- - increase Thymidylate synthetase activity
- - reduce drug sensitivity
-
Capecitabine - Adverse effect
Hand/foot syndrome
-
Cytosine arabinoside (ara-C)
- MoA: pyrimidine analogue - incorporates into DNA
- AE: BM suppression, mucositis, Neurotoxicity (cerebellar dysfunction)
- Inc. cytidine deaminase (inactivator)
- dec. deoxycytidine kinase (activator)
- dec. affinity
-
Gemcitabine
MoA: cytosine analogue
-
6-mercaptopurine (6-MP)
6-thioguanine (6-TG)
- MoA: inhibit PRPP & HGPRT (purine cycle) => inhibit DNA synthesis
- Use: Leukemias
- AE: BMS, mucositis, GI toxicity
- Resistance: increase XO, decrease affinity
-
Allopurinol
- MoA:
- - inhibits Xanthine Oxidase
- - inhibits PRPP
- Use: Gout prophylaxis, enhance cytotoxic effect of purine analogues (6-MP)
-
Fludarabine
- MoA: adenosine analogue
- Use: low grade lymphoma
-
Cladribine
- MoA: adenosine analogue
- Use: Hairy cell leukemia
-
what is the interaction between Allopurinol with 6-MP and 5-FU
- increase activity of 6-MP
- decrease activity of 5-FU
-
Hydroxyurea
- MoA: inhibits ribonucleotide reductase (converts RNA to DNA)
- Use: CML & Sickle cell disease
- AE: BMS, Diarrhea, N&V
-
Anthracyclines (-rubicin)
- Doxorubicin
- Epirubicin
- Daunorubicin
- Idarubicin
- MoA:
- - intercalate DNA
- - inhibit Topoisomerase 2
- - generates ROS
- Use: variety of cancers
- AE: Cardiac toxicity, BMS, alopecia, N&V, Secondary malignancy
- Resistance: MDR
-
Anthracenedione
- Mitoxantrone
same as anthracyclines, but less active and toxicity
-
Dactinomycin
- MoA: intercalate DNA
- Use: Pediatric tumor (Wilm's, RB, Neurofibromatosis)
- AE: BMS, severe vesicant
-
Mitomycin
- MoA: alkylator, cause cross linking
- AE: TTP
-
Bleomycin
- MoA: intercalate DNA (G2 only!!!)
- Use: Testicular ca.
- AE: Lung toxicity, liver toxicity, anaphylactic reaction, Skin toxicity
- Resistance: MDR
-
Vinca alkaloids
- vincristine, vinblastine, vindesine, vinorelbine
- MoA: cause MT depolymerization
- AE: Peripheral neuropathy (motor irreversible)
-
Taxanes
- paclitaxel, docetaxel
- MoA: prevent MT depolymerization
- AE: BMS, allergy, myalgia, arthralgia, neuropathy, skin & nail toxicity (use steroids to prevent these effects)
- Resistance: MDR (except carbazitaxel)
-
Podophyllotoxin
- etoposide, teniposide
- MoA: inhibit topoisomerase-2
- AE: BMS, hypotension (give large dose)
- Resistance: MDR
-
Camptothecin
- irinotecan, topotecan
- MoA: inhibit topoisomerase-1
- AE: BMS, excessive diarrhea, acute cholinergic side effects (use atropine)
- Resistance: MDR
-
Platinums
- cisplatinum(1), carboplatinum(2), oxaliplatinum(3)
- MoA: alkylator
- Use: Testicular ca. (cisplatinum)
- AE: neurotoxicity, nephrotoxicity(1), BMS(2), cold intolerance(3)
- Resistance: MDR, increase thiol, increase DNA repair
-
Preventions of Nephrotoxicity in platinums
- hydration
- replace K & Mg
- amifosine - remove cisplatin
-
Prevention of neurotoxicity in platinums
- Ca2+ & Mg2+ replacement
- Avoid cold
-
L-Asparaginase
- MoA: hydrolyses circulating asparagine (tumor cells can't make asparagine)
- Use: pediatric ALL
-
Arsenic trioxide
Use: combination with ATRA in PML
-
Anti-estrogen therapy
- Tamoxifen
- Aromatase inhibitors
- Progestins
- LHRH/GnRH
-
Tamoxifen
- MoA: block estrogen on cancer cells
- Use: breast ca.
- AE:
- - thromboemolism => retinopathy
- - endometrial ca.
- Resistance:
- - change in ER
- - ER- cell selection
-
Aromatase inhibitors
- Anastrozole
- Letrozole
- Exemestane
- MoA: inhibit aromatase (dec. estrogen)
- only used in menopausal settings
- Use: Breast ca.
- AE:
- - osteoporosis => arthralgias
- - hot flushes
-
Progestins
- Megestrol
- Medroxyprogesterone
- MoA: act like progesterone, decrease estrogen receptors
- Use: breast ca.
-
LHRH/GnRH
- Leuprolide
- Goserilin
- MoA: inhibits LH & FSH release
- Use: Breast ca., Prostate ca.
-
Anti-androgen therapy
- Flutamide, Bicalutamide
- LHRH
- Abiterone
-
Flutamide, Bicalutamide
- MoA: androgen blocker
- Use: prostate ca.
- AE:
- - impotence
- - andropause
- - hot flushes
- Resistance:
- - change in androgen receptors
- - receptor neg cell selection
-
Abiterone
- MoA: inhibits 17a-hydroxylase; decrease androgen & corticosteroid
- Use: prostate ca.
-
Rituxumab
- MoA: anti-CD20
- Use: B cell lymphoma
-
Alemtuzumab
- MoA: anti-CD52
- Use: B cell lymphoma
-
Ipilimumab
- MoA: anti-CTLA-4
- Use: metastatic melanoma
-
Trastuzumab/Herceptin
- MoA: anti-EGFR
- Use: Her-2/neu breast cancer
- AE: cardiac toxicity (reversible), skin rash
- (avoid usage with Doxorubicin)
-
Cetuximab
- MoA: anti-EGFR
- Use: SCC, wild type k-ras colon cancer
- AE: skin rash (steroids)
-
Panitunumab
- MoA: anti-EGFR
- Use: wild type k-ras colon cancer
- AE: skin rash (steroids)
-
Bevacizumab
- MoA: anti-VEGF
- Use: colon cancer
- AE: cause ineffective wound healing
-
Interferons
- MoA: interferes with cell replication
- AE: flu-like symptoms, Hepatotoxicity, BMS
-
Interleukins
- MoA: stimulates cytotoxic T-cell
- AE: leaky membrane (edema)
-
TNF-a
- MoA: stimulate apoptosis
- AE: inflammatory response
-
Lapatinib
- MoA: Her-2 TKI
- Use: breast ca.
-
Gefitinib, Erlotinib
- MoA: non-Her2 TKI
- Use: lung ca.
-
Sunitinib
- MoA: VEGF TKI
- Use: renal cell ca.
-
Sorafinib
- MoA: VEGF TKI
- Use: Hepatocellular ca.
-
Imatinib, Nilotinib
- MoA: Bcr-abl oncogene product
- Use: CML, GIST
-
Vemurafenib
- MoA: R-raf inhibitor, RAS pathway inhibitor
- Use: metastatic melanoma
-
Sirolimus, Temsirolimus, Everolimus
- MoA: M-TOR inhibitor
- Use: transplant immunosuppression
-
Bortezomib
- MoA: proteosome inhibitor
- Use: MM, mantel cell lymphoma
-
Thalidomide
- MoA: inhibit angiogenesis
- Use: MM
- AE: birth defect (no limbs)
-
Drugs that cause Alopecia
- Anthracycline
- Taxanes
- Alkylating agents
-
Drugs that cause Nausea & vomiting
- Platinum
- Anthracyclines
- Nitrogen mustard
-
Drugs that cause Mucositis
Anti-metabolites
-
Drugs that cause Extravasation/vesicants
- Alkylators
- Naturally occurring products
-
Drugs that cause Discoloration
Anti-metabolites
-
Drugs that cause Hand-Foot syndrome
Capecitabine
-
Drugs that cause Acneiform
-
Drugs that cause Pharyngolaryngeal dysesthesia
Oxaliplatin
-
Drugs that cause Cholinergic syndrome
Irinotecan
-
Drugs that cause Neurologic toxicity
- Vinca alkaloids
- Taxanes
- Platinum
-
Drugs that cause Cardiac toxicity
- Anthracyclines
- 5-FU
- cyclophosphamide
-
Drugs that cause Nephrotoxicity
- cisplatinum
- Mitomycin
- Cyclophosphamide
-
Drugs that cause Pulmonary toxicity
- Bleomycin
- Gemcitabine
- Busulfan
-
Drugs that cause Hematologic toxicity
-
Drugs that cause TTP
Mitomycin
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