ANTINEOPLASTIC_FINAL_CARDS.txt

Tx MYELOSUPPRESSION

EPO REPLACEMENT

IV OR SC

• Tx
• --FATIGUE
• --SOB

Tx MYELOSUPPRESSION

LIKE EPO ALFA BUT LONGER HALF LIFE

Tx THROMBOCYTOPENIA

IL-11 = Megakaryocyte growth factor

• Tx
• Thrombocytopenia
• (no platelets) → Hemorrhage

MYELOSUPPRESSION

• Granulocyte colony-stimulating
• factor (G-CSF)

• Tx
• Leukopenia

• i.e. Neutropenia
• (Neutrophil count < 1000)

• --infections
• --fever

• *Na dir neutrophils count during a cycle
• of chemo is the most important value

MYELOSUPPRESSION

Granulocyte –Macrophage colony-stimulating factor (GM-CSF)

Tx MYELOSUPPRESSION

FOR BM "RESCUE" for pts taking methotrexate

• nL CELLS TAKE UP LEUCOVORIN (FOLINIC ACID) TO SYNTH THF BUT TUMOR CELLS CAN'T

ALKYLATING AGENT

• Polyfunctional alkylating agents: CCNS
• Nitrogen mustards

ALKYLATING AGENT

OTHER ALKYLATING AGENT: CCNS

CNS DEPRESSION

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

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)

ALKYLATING AGENT

Polyfunctional alkylating agent: CCNS

Given p.o.

• ADVERSE
• --PULM FIBROSIS
• --SKIN PIGMENTATION
• --ADRENAL INSUFFICIENCY

ALKYLATING AGENT

Nitrosureas alkylating agent: CCNS

crosses blood-brain barrier → Tx 1o CNS tumors

CROSS-LINK DNA VIA ALKYLATION

REQUIRES BIOACTIVATION

ESTROGEN RECEPTOS IN TUMOR TISSUE

ACT ON PITUITARY TO INH RELEASE OF LH AND FSH

DEC LH DECREASES ESTROGEN SYNTH BY OVARIES

ALKYLATING AGENT: CCNS

HODGKIN'S DISEASE = B CELL NEOPLASM

"ABVD"

• Adriamycin
• (doxorubicin)

Bleomycin

Vinblastine

Dacarbazine

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

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

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

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

ANTIMETABOLITES -- ALTERS GENE EXPRESSION

CCS S-PHASE

Pyrimidine analog

Inhb enz DNA methyltransferase

METHYLATION TURNS OFF TUMOR SUPPRESSOR GENES

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

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

TAMOXIFEN -- SERM

or

LETROZOLE -- AROMATASE INH

• S/E TAMOXIFEN
• --INC ENDOMETRIAL CANCER
• --MENOPAUSAL SYMPTOMS

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

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

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

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

TAXANES

CCS - M PHASE

• MOA
• “Spindle poisons”

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

Tx CHRONIC LYMPHOCYTIC LEUKEMIA & HODGKIN'S LYMPHOMA

MOA - APOPTOSIS IN NON-DIVIDING CELLS

• S/E
• --IMMUNOSUPPRESSION
• --ADRENAL SUPPRESSION
• --PSYCHOSIS

INC TUMOR CELL DEATH BY INC DOSE ANTIMETABOLITES

INC TUMOR DEATH BY INC EXPOSURE TIME NOT DOSE

MISCELLANEOUS

CCS - S PHASE

• MOA
• 1. Inhb ribonucleotide reductase

2. Depletion of deoxynucleoside triphosphate → Prevents DNA synth

• ----------------------------------
• TOX
• -MYELOSUPPRESSION

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.

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).

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

MONOCLONAL ANTIBODIES

• MOA
• Binds CD20 Ag expressed on all malignant B cell lymphocytes

SLOWS TUMOR GROWTH AND DEPLETES THE PERIPH B-CELL POPULATION

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

MONOCLONAL ANTIBODIES

• MOA
• · Blocks EGFR (HER1) in colorectal cancer
• (60-75% pts express)

Block cell prolif, survival & angiogenesis

• 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

Anthracyclines = doxorubicin

BLEOMYCIN

CISPLATIN

CYCLOPHOSPHAMIDE

CYTARABINE

--Vincristine

--Paclitaxel

5-FU

Asparaginase

Capecitabine

Carmustine (BCNU)

Lomustine (CCNU)

Also act in G0 → Tx 1o tumors of CNS

Cisplastin

Carboplatin

Procarbazine

Doxorubicin aka Hydroxydaunorubicin

Dactinomycin (Actinomycin D)

PREDNISONE

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)

• Corticosteroids suppress mitosis & cause
• apoptosis of non-dividing cells

G0 = 40% CELL CYCLE

Antimetabolites:

• 1) 5-fluorouracil (5-FU)
• 2) 6-mercaptopurine (6-MP)
• 3) Methotrexate
• 6) Cytarabine
• 7) Hydroxyurea

S-PHASE = 40% CELL CYCLE

• 1. Bleomycin
• 2. Etoposide
• 3. Teniposide

G2-PHASE = 18% CELL CYCLE

1. Vincristine

2. Vinblastine

• 1. Paclitaxel
• 2. Docetaxel
• 3. Vincristine
• 4. Vinblastine

2% OF CELL CYCLE

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.”

• 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

ADVERSE / TOX

1. Myelosuppression & immunosuppression → GRANULOCYTIC LEUKEMIA

2. Sterile hemorrhagic cystitis. co-tx with Na-2-mercaptoethane sulfate (mesna) free-red scavenger