-
EPOETIN ALFA
Tx MYELOSUPPRESSION
EPO REPLACEMENT
IV OR SC
-
DARBEPOETIN
Tx MYELOSUPPRESSION
LIKE EPO ALFA BUT LONGER HALF LIFE
-
OPRELVEKIN
Tx THROMBOCYTOPENIA
IL-11 = Megakaryocyte growth factor
- Tx
- Thrombocytopenia
- (no platelets) → Hemorrhage
-
FILGRASTIM
MYELOSUPPRESSION
- Granulocyte colony-stimulating
- factor (G-CSF)
- i.e. Neutropenia
- (Neutrophil count < 1000)
- *Na dir neutrophils count during a cycle
- of chemo is the most important value
-
SARGRAMOSTIM
MYELOSUPPRESSION
Granulocyte –Macrophage colony-stimulating factor (GM-CSF)
-
LEUCOVORIN
Tx MYELOSUPPRESSION
FOR BM "RESCUE" for pts taking methotrexate
- nL CELLS TAKE UP LEUCOVORIN (FOLINIC ACID) TO SYNTH THF BUT TUMOR CELLS CAN'T
-
MECHLORETHAMINE
ALKYLATING AGENT
- Polyfunctional alkylating agents: CCNS
- Nitrogen mustards
-
PROCARBAZINE
ALKYLATING AGENT
OTHER ALKYLATING AGENT: CCNS
CNS DEPRESSION
-
CYCLOPHOSPHAMIDE
ALKYLATING AGENT
- Polyfunctional alkylating agent: CCNS
- Nitrogen mustard
- Given p.o.
- ---------------------------
- ADVERSE / TOX
Toxic to urinary bladder
· Myelosuppression
· Acrolein metabolite → non-hemorrhagic & hemorrhagic cystitis → hydration & freq urination nec to
- ----Co-admin mesna (Na-2-mercaptoethane sulfate): free-radical scavenger binds acrolein metabolite → prevents GU damage (& rapidly cleared by kidneys)
- ----“hematuria w/o bacteria”
ALLOPURINOL prolongs t1/2 and inc toxicity
-
NA-2-MERCAPTOETHANE
SULFATE (MESNA)
ALKYLATING AGENT
TO PREVENT GU DAMAGE CAUSED BY CYCLOPHOSPHAMIDE
- Co-admin mesna (Na-2-mercaptoethane sulfate):
- --Free-radical scavenger binds acrolein metabolite
- → prevents GU damage (& rapidly cleared by kidneys)
-
BUSULFAN
ALKYLATING AGENT
Polyfunctional alkylating agent: CCNS
Given p.o.
- ADVERSE
- --PULM FIBROSIS
- --SKIN PIGMENTATION
- --ADRENAL INSUFFICIENCY
-
CARMUSTINE (BCNU)
LOMUSTINE
ALKYLATING AGENT
Nitrosureas alkylating agent: CCNS
crosses blood-brain barrier → Tx 1o CNS tumors
CROSS-LINK DNA VIA ALKYLATION
REQUIRES BIOACTIVATION
-
WHICH TYPE OF RECEPTOR MUST BE PRESENT FOR Tx OF BREAST CANCER w GnRH ANALOGS LEUPROLIDE AND GOSERELIN?
ESTROGEN RECEPTOS IN TUMOR TISSUE
ACT ON PITUITARY TO INH RELEASE OF LH AND FSH
DEC LH DECREASES ESTROGEN SYNTH BY OVARIES
-
DACARBAZINE
ALKYLATING AGENT: CCNS
HODGKIN'S DISEASE = B CELL NEOPLASM
"ABVD"
Bleomycin
Vinblastine
Dacarbazine
-
CISPLATIN
ALKYLATING AGENT
Platinum alkylating agents: CCNS
Tx TESTICULAR AND LUNG CARCINOMAS
FORMS INTRA AND INTERSTRAND CROSS LINKS AT N7 OF GUANINE VIA HYDROYSIS OF CHLORIDE GROUPS = INH DNA REP AND TRANSCRIPTION
REPLACEMENT OF CHLORIDE w WATER FORMS ACTIVE DRUG
S/E = NEPHROTOX WHICH IS DEC BY Cl- DIURESIS bc Cl- STABILIZES THE PLATIN COMPLEX
RENAL TOX CAUSES LOSS OF Mg, Ca, K, AND PHOS
CN VIII DAMAGE
-
METHOTREXATE
ANTIMETABOLITES
CCS S-PHASE
Tx leukemias and sarcomas
MOA
Structurally sim to folic acid. Given p.o. or intrathecal.
- 1. Forms highly-active polyglutamate
- compounds which persist in cancer cells.
- 2. Reversibly inhb dihydrofolate
- (DHF) reductase → prevents synth of tetrahydrofolate (THF)
3. Lack of THF → decr synth of thymidylate, purine nucleotides & amino acids: Ser & Met.
- ---------------------------------------------------
- ADVERSE
- 1. Myelosuppression
- --Bone marrow can be rescued by treatment w/
- leucovorin (folinic acid)
- ---------------------------
- RESISTANCE
- --FOLATE TRANSPORTER --> DEC UPTAKE
- --DHF REDUCTASE --> MUT TARGET
-
5-FLUOROURACIL
ANTIMETABOLITES
CCS S-PHASE
Tx Colon cancer
Pyrimidine (cytosine, uracil & thymine) analog
1. 5-FU converted to F-dUMP irreversibly inhb thymidylate synthetase.
2. Lack of thymidylate blocks DNA synth: “thymineless death”
incorp into mRNA → prevents normal tsl of mRNA
ORAL AND GI ULCERATION
- RESISTANCE
- --DIHYDROPYRAMIDINE --> INACTIVATION
- --THYMIDYLATE SYNTHETASE --> MUT OF TARGET
NO LEUCOVORIN RESCUE
-
CYTARABINE (ARA-C)
ANTIMETABOLITES
CCS S-PHASE
Pyrimidine analog
Phosphorylated ara-CTP → Inhb DNA polymerase
- Also phosphorylated ara-CTP incorporated into
- DNA & RNA
- --------------------
- TOXIC TO CNS
MEGALOBLASTOSIS
RESISTANCE- --CYTIDINE DEAMINASE--> INACTIVATES
-
AZACITIDINE
ANTIMETABOLITES -- ALTERS GENE EXPRESSION
CCS S-PHASE
Pyrimidine analog
Inhb enz DNA methyltransferase
METHYLATION TURNS OFF TUMOR SUPPRESSOR GENES
-
6-mercaptopurine
ANTIMETABOLITES
CCS S-PHASE
- 2. Decr HGPRT actvy → 6-MP & 6-TG resistance
- ---------------------------------------------
- ADVERSE / TOX
- 1. Xanthine oxidase degrades 6-MP.
- ----Allopurinol (anti-gout drug) inhb xanthing oxidase → incr 6-MP toxicity → Must decr 6-MP dose.
- ----6-TG not metab by xanth. oxids.
2. Myelosuppression
-
BLEOMYCIN
ANTIBIOTIC DRUG
CCS G2-PHASE
peptide antibiotic
1. Binds to DNA → forms O2 free radicals → single- & double-stranded breaks.
2. Block DNA synth
3. Fragmentation of DNA → Chromosomal abnormalities
- 4. Cancer cells accumulate in G2
- -----------------------------------------------
- ADVERSE / TOX
- 1. Pulmonary fibrosis*
- ----Begin w/ dry cough, fine rales & difuse basilar infiltrates on CXR.
little bone marrow depression
-
DRUG w ANTI-ESTROGENIC EFFECTS FOR Tx OF BREAST CANCER?
TAMOXIFEN -- SERM
or
LETROZOLE -- AROMATASE INH
- S/E TAMOXIFEN
- --INC ENDOMETRIAL CANCER
- --MENOPAUSAL SYMPTOMS
-
DACTINOMYCIN
ANTIBIOTIC DRUG aka ACTINOMYCIN D
WILM's TUMOR
1. Intercalates into ds-DNA btwn G≡C pairs.
2. DNA-dependent RNA synth impaired → Block protein synth.
3. (DNA replication is little affected)
BONE MARROW SUPPRESSION
-
DOXORUBICIN & DAUNORUBICIN
ANTIBIOTIC DRUG aka HYDROXYDUNORUBICIN
- CCNS
- ·
- Anthracycline
- antibiotic drug
1. Intercalates into DNA → blocks DNA & RNA synth
4. Generate semiquinone & O2 free radicals (TOX)
- 5. Cells die in G2
- --------------------------------
- ADVERSE / TOX
- --♥Heart: Free radicals damage
- --BONE MARROW DEPRESSION
- --RED URINE -- NOT HEMATURIA
-
ETOPOSIDE
CCS LATE S-G2 PHASE
1. Stabilize bond btwn Topo II & DNA
2. Inhb Topo II → Double strand breaks remain
- 3. DNA degraded
- ---------------------------------------
ADVERSE / TOX
1. Dose-limiting Myelosuppression
-
VINCRISTINE
&
VINCBLASTINE
VINCA ALKALOIDS
CCS: LATE G2-EARLY-M PHASE
ON USMLE -- M PHASE
MOA
“Spindle poisons”
- 3. Cells arrest in metaphase b/c mitotic
- filaments cannot form.
- -------------------------------------
- ADVERSE
- VINBLASTINE
- --MYELOSUPPRESSION
- --AREFLEXIA
- --ALOPECIA
- VINCRISTINE:
- --AREFLEXIA
- --PERIPH NEURITIS
- --MUSC WEAKNESS
- --PARALYTIC ILEUS
- --ALOPECIA
-
PACLITAXEL
TAXANES
CCS - M PHASE
Tx ovarian and breast cancer
1. Enhances polymerization of tubulin
2. Promotes microtubule assembly
Causes mitotic arrest b/c anaphase cannot occur.
COLCHICINE, GRISEOFULVIN AND MEBENDAZOLE ALSO BLOCK MICROTUBULE FUNCTION
- S/E
- --BONE MARROW DEPRESSION
- --PERIPH NEUROPATHY
- RESISTANCE
- --b-TUBILIN ISOTYPES --> MUT TARGET
-
PREDNISONE
Tx CHRONIC LYMPHOCYTIC LEUKEMIA & HODGKIN'S LYMPHOMA
MOA - APOPTOSIS IN NON-DIVIDING CELLS
- S/E
- --IMMUNOSUPPRESSION
- --ADRENAL SUPPRESSION
- --PSYCHOSIS
-
MOA OF RADIATION AND ALKYLATING AGENTS
INC TUMOR CELL DEATH BY INC DOSE ANTIMETABOLITES
INC TUMOR DEATH BY INC EXPOSURE TIME NOT DOSE
-
HYDROXYUREA
MISCELLANEOUS
CCS - S PHASE
- MOA
- 1. Inhb ribonucleotide reductase
2. Depletion of deoxynucleoside triphosphate → Prevents DNA synth
- ----------------------------------
- TOX
- -MYELOSUPPRESSION
-
IMATINIB
MISCELLANEOUS
- MOA
- Blocks binding of ATP to Bcr-Abl tyrosine kinase → Inhb phosphorylation of kinase substrate (inhb oncogene product)
Philidelphia (Ph) chromosome w/ t(9:22) → codes for fusion oncoprotein Bcr-Abl, a tyrosine kinase which is essential for prolif/survival of abnorm WBCs → chronic myelocytic (myelogenous) leukemia.
-
BORTEZOMIB
ALTERS GENE EXPRESSION
ENHANCES APOPTOSIS -- Tx MULTIPLE MYELOMAS (PLASMA CELL CANCERS)
MOA
1. Inhb actvy of 26S proteasome
2. Prevents degradation of IκB (inhibitor)
3. Enhances apoptosis by preventing action of NF-κB (nuclear factor kappa: upreg DNA tsc, cell survival, inhb apoptosis)
Treats multiple myeloma (plasma cell cancers).
-
LEVAMISOLE
IMMUNOMODULATING AGENT
RESTORES DEPRESSED IMMUNE FUNC IN B CELLS, T CELLS, MONOCYTES AND MACROS
POTENTIATES ANTINEOPLASTIC EFFECTS OF 5-FU IN Pts w COLON CANCER
-
RITUXIMAB
MONOCLONAL ANTIBODIES
- MOA
- Binds CD20 Ag expressed on all malignant B cell lymphocytes
SLOWS TUMOR GROWTH AND DEPLETES THE PERIPH B-CELL POPULATION
-
TRASTUZUMAB
MONOCLONAL ANTIBODIES
- MOA
- · Blocks EGFR coded by HER2/neu (ErbB-2) gene
- Treats breast cancer tumors (+) for HER2/neu
- ----------------------------------
ADVERSE TOX
CARDIAC DYSFUNC, ESP IF Tx w DOXORUBICIN
-
CETUXIMAB
MONOCLONAL ANTIBODIES
- MOA
- · Blocks EGFR (HER1) in colorectal cancer
- (60-75% pts express)
Block cell prolif, survival & angiogenesis
-
CELL CYCLE
- G0
- Differentiation. Resting phase.
- G1 Synthesis of compounds needed to synthesize
- DNA (18-30 hours)
- S DNA replication & repair. Chromosomes double (16-20 hours)
- --HYDROXYURIA
- --5-FU
- --6-MP, TP
- --METHOTREXATE
- --CYTARABINE
- G2 Synthesis of molecules needed for mitosis
- (2-10 hours)
- --BLEOMYCIN
- --ETOPOSIDE
- M Mitosis (0.5-1 hour)
- --VINCRISTINE/BLASTINE
- --PACLITAXEL
-
HEAT TOXICITY
Anthracyclines = doxorubicin
-
-
-
URINARY BLADDER TOX
CYCLOPHOSPHAMIDE
-
-
PNS TOX
--Vincristine
--Paclitaxel
-
-
-
DERM TOX
(skin/nails)
Capecitabine
-
Nitrosoureas alkylating agents: Cell Cycle Non-Specific (CCNS)
Carmustine (BCNU)
Lomustine (CCNU)
Also act in G0 → Tx 1o tumors of CNS
-
PLATINUM ALKYLATING AGENTS: Cell Cycle Non-Specific (CCNS)
Cisplastin
Carboplatin
-
OTHER ALKYLATING AGENTS: CCNS
Procarbazine
-
Anthracycline antibiotic drugs: CCNS
Doxorubicin aka Hydroxydaunorubicin
-
ANTIBIOTIC DRUGS: CCNS
Dactinomycin (Actinomycin D)
-
GLUCOCORTICOIDS: CCNS
PREDNISONE
-
CCNS
CELL CYCLE NON-SPECIFIC
1) Can work at any step in the cell cycle, including G0
2) Cells are more sensitive in late G1 & S phases b/c polynucleotides are more susceptible to alkylation in the unpaired state than in the helical form.
3) Toxicity ~ expressed when cells enter S phase → Block progression through cell cycle.
e.g. doxorubicin: intercalates into DNA → DNA strand scission (single & double strand breaks) via inhibition of topoisomerase II, (cells die in G2)
-
G0-PHASE: CCS DRUGS
- Corticosteroids suppress mitosis & cause
- apoptosis of non-dividing cells
G0 = 40% CELL CYCLE
-
S-PHASE: CCS DRUGS
Antimetabolites:
- 1) 5-fluorouracil (5-FU)
- 2) 6-mercaptopurine (6-MP)
- 3) Methotrexate
- 6) Cytarabine
- 7) Hydroxyurea
S-PHASE = 40% CELL CYCLE
-
G2-PHASE: CCS DRUGS
- 1. Bleomycin
- 2. Etoposide
- 3. Teniposide
G2-PHASE = 18% CELL CYCLE
-
LATE G2 / EARLY M-PHASE: CCS DRUGS
1. Vincristine
2. Vinblastine
-
M-PHASE: CCS DRUGS
- 1. Paclitaxel
- 2. Docetaxel
- 3. Vincristine
- 4. Vinblastine
2% OF CELL CYCLE
-
CCS: CELL CYCLE SPECIFIC DRUGS
1. Inhb cell division by acting during a specific cell cycle phase. Cells in sensitive phase are killed.
2. CCS drugs most effective in hematologic cancers & tumors w/ a relatively large # of cells in the “growth fraction.”
-
ALKYLATING AGENTS MOA
- 1. Damage DNA via cross-linking (bifunctional drugs w/ 2 reactive groups)
- --OR--
- 2. Damage DNA via single-strand breaks (monofunctional drugs w/ 1 reactive group)
Primary site of DNA alkylation is N7 position of Guanine. O6 also attacked.
- Alkylation of DNA:
- 1. Inhb synthesis of DNA, RNA & proteins
- 2. Causes misreading of DNA
- ------------------------------------------
ADVERSE / TOX
- 1. Myelosuppression & immunosuppression →
- dose-limiting toxicity
-
ALKYLATING AGENTS ADVERSE / TOX
(Cyclophosphamide)
ADVERSE / TOX
1. Myelosuppression & immunosuppression → GRANULOCYTIC LEUKEMIA
2. Sterile hemorrhagic cystitis. co-tx with Na-2-mercaptoethane sulfate (mesna) free-red scavenger
|
|