ANTINEOPLASTIC_DRUGS_MS2

MYELOSUPPRESSION

EPO REPLACEMENT

IV OR SC

• Tx
• --FATIGUE
• --SOB

Tx MYELOSUPPRESSION

LIKE EPO ALFA BUT LONGER HALF LIFE

MYELOSUPPRESSION

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

• Rapid recovery (14-21 days)
• or
• Delayed recovery (50+ days)

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

MYELOSUPPRESSION

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

MYELOSUPPRESSION

FOR BM "RESCUE" for pts taking methotrexate

ALKYLATING AGENT

• Polyfunctional alkylating agents: CCNS
• Nitrogen mustards

ALKYLATING AGENT

OTHER ALKYLATING AGENT: CCNS

GIVEN PO

ALKYLATING AGENT

• Polyfunctional alkylating agent: CCNS
• Nitrogen mustard

• Given p.o.
• ---------------------------

ADVERSE / TOX

Toxic to urinary bladder

· Myelosuppression

· Immunosuppression: used in organ transplant

· Highly emetic

• · Acrolein metabolite → non-hemorrhagic & hemorrhagic cystitis → hydration & freq urination nec to prev damage to GU tract.
• ----Co-admin mesna (Na-2-mercaptoethane sulfate): free-radical scavenger binds acrolein metabolite → prevents GU damage (& rapidly cleared by kidneys)
• ----“hematuria w/o bacteria”

SIADH: could cause H2O intox b/c intake incr’d to prev GU damage

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

ALKYLATING AGENT

Nitrosureas alkylating agent: CCNS

Given i.v.

*Also act in G0 & crosses blood-brain barrier → Tx 1o CNS tumors

• ADVERSE
• --PULM FIBROSIS

ALKYLATING AGENT

Other alkylating agent: CCNS

Given p.o.

Crosses blood-brain barrier

Does NOT need bioactivation

Tx 1o & 2o brain tumors

ALKYLATING AGENT

HODGKIN'S DISEASE = B CELL NEOPLASM

"ABVD"

• Adriamycin
• (doxorubicin)

Bleomycin

Vinblastine

Dacarbazine

ALKYLATING AGENT

Platinum alkylating agents: CCNS

• Given i.v.
• --------------------------------------
• ADVERSE

Highly emetic → pretreat w/ 5-HT3 blocker + dexomethasone

• --Nephrotoxicity:
• ----Pre- & post-treat hydration w/ 0.9% saline → decr toxicity

----Carboplatin less renal & GI toxic < cisplatin.

High frequency hearing loss

Neurotoxicity = sensory neuropathy

ALKYLATING AGENT

• SAME AS CISPLATIN
• Platinum alkylating agents: CCNS

• Given i.v.
• --------------------------------------

ADVERSE

Highly emetic → pretreat w/ 5-HT3 blocker + dexomethasone

• --Nephrotoxicity:
• ----Pre- & post-treat hydration w/ 0.9% saline → decr toxicity
• ----Carboplatin less renal & GI toxic < cisplatin.

High frequency hearing loss

Neurotoxicity = sensory neuropathy

ANTIMETABOLITES

CCS S-PHASE

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.

• 4. Also inhb several folate-dependent enzs (thymidylate synthetase & glycinamide ribonucleotide formyltransferase (GARFT)) involved in synth of both purines & thymidylate.
• ---------------------------------------------------
• ADVERSE

• 1. Myelosuppression
• --Bone marrow can be rescued by treatment w/
• leucovorin (folinic acid)

2. Nephrotoxicity

ANTIMETABOLITES

CCS S-PHASE

Pyrimidine (cytosine, uracil & thymine) analog

*Given i.v., topical for actinic keratoses & basal cell cancers

1. Metabolite 5-fluoro-2-deoxyuridine 5-phosphate (F-dUMP) irreversibly inhb thymidylate synthetase.

2. Lack of thymidylate blocks DNA synth: “thymineless death”

• 3. 5-fluorouridine triphosphate incorp into mRNA → prevents normal tsl of mRNA
• -------------------------------------------------

ADVERSE / TOX

1. Toxic to eyes

2. Pts w/o enz dihydropyrimidine dehydrogenase (DpD) → cannot inactv 5-FU

3. Myelosuppression

4. Stomatitis, mucositis & diarrhea

5. Hyperpigmentation

6. Photosensitivity

7. “Hand-food” syndrome: Painful erythematous desquamation of palms & soles.

ANTIMETABOLITES

CCS S-PHASE

Pyrimidine analog

Phosphorylated ara-CTP → Inhb DNA polymerase

• Also phosphorylated ara-CTP incorporated into
• DNA & RNA

TOXIC TO CNS

ANTIMETABOLITES

CCS S-PHASE

Pyrimidine analog

• Inhb enz DNA methyltransferase → turns on tumor
• suppressor genes.

ANTIMETABOLITES

CCS S-PHASE

• Purine (guanine & adenine) analog
• 1. Enz hypoxanthine guanine phosphoribosyl transferase (HGPRT) converts 6-MP & 6-TP → Inhb purine synthesis

• 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

Given i.v., i.m., s.c. & intravacavitary (for malignant effusions)

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.
• ----Progresses to pulm. fibrosis.

2. Lethal anaphylactic rxns, esp w/ lymphoma

3. Fever & chills w/in 48 hours

4. Hyperpigmentation of elbows & knees

5. Hyperkeratosis of palms

6. No bone marrow depression

ANTIBIOTIC DRUG aka ACTINOMYCIN D

1. Intercalates into ds-DNA btwn G≡C pairs.

2. DNA-dependent RNA synth impaired → Block protein synth.

• 3. (DNA replication is little affected)
• --------------------------------
• ADVERSE / TOX

1. Myelosuppression

2. Immunosuppression

3. Radical “recall”: skin inflammation at previously irradiated sites

ANTIBIOTIC DRUG aka HYDROXYDUNORUBICIN

CCNS

• ·
• Anthracycline
• antibiotic drug

1. Intercalates into DNA → blocks DNA & RNA synth

2. DNA strand scission (ss- & ds-DNA breaks) via inhbn of Topo II

3. Alters ion transport through membranes

4. Generate semiquinone & O2 free radicals

• 5. Cells die in G2
• --------------------------------
• ADVERSE / TOX

• 1. ♥Heart: Free radicals damage
• ----Acute: PVCs, transient changes in ST segment & T-wave
• ----Chronic: cumulative,
• dose-related cardiomyopathy → ♥ failure
• ----TOTAL cumulative dose determines likelihood of cardiac damage

2. Myelosuppression: short duration & rapid recovery

3. Stomatitis

4. Radiation recall

5. Alopecia

EPIPODOPHYLLOTOXINS

CCS LATE S-G2 PHASE

1. Stabilize bond btwn Topo II & DNA

2. Inhb Topo II → Double strand breaks remain

3. DNA degraded

--Topoisomerases cut ss- or ds-DNA to allow strand(s) to unwind.

§ Breaks are religated after unwinding.

§ Topo I: cuts/religates ss-DNA

§ Topo II: cuts/religates ds-DNA

• § Topo I & II necess for DNA replication & RNA
• tsc.

• --Topo II necess to complete mitosis.
• ---------------------------------------
• ADVERSE / TOX

1. Dose-limiting Myelosuppression

2. Anaphylaxis

3. Fever

4. Hypo-or hypertension

5. 2* leukemias

CAMPTOTHECINS

CCNS

• Inhb Topo I → DNA damage
• -------------------------------------
• ADVERSE / TOX

1. Myelosuppression

2. Occasional diarrhea

VINCA ALKALOIDS

CCS: LATE G2-EARLY-M PHASE

ON USMLE -- M PHASE

MOA

“Spindle poisons”

• 1. Bind to dimeric tubulin → prevent further
• polymerization (→ prevent assembly of microtubules)

2. Already formed microtubules depolymerize.

• 3. Cells arrest in metaphase b/c mitotic
• filaments cannot form.

§ Microtubules (heterodimers of α- & β-tuublin) form mitotic spindle.

§ Mitotic spindle separates the duplicate set of chromosomes during cell division.

• § Microtubules have “dynamic instability” b/c
• constant remodeling

• --Remodeling involves constant incorp of free
• dimmers & simult release of dimmers into solb tubulin pool
• -----------------------------
• OTHER INFO

• Over expression of MDR1 & Pgp170 genes → Incr
• efflux pumps → cross-resistance btwn different classes of drugs

• e.g. taxanes (paclitaxel) & vinca alkaloids
• -------------------------------------
• ADVERSE / TOX

VINBLASTINE -- DOSE-LIMITING MYELOSUPPRESSION

• VINCRISTINE:
• 1. Dose-limiting Neurotoxicity:
• o loss of tendon reflexes

o paresthesias (feet & hands) in a “stocking-glove” distrb (not above knee or elbow)

o autonomic dysfunction: constipation, orthostatic hypotension

2. Myelosuppression (less)

TAXANES

CCS - M PHASE

• MOA
• “Spindle poisons”

1. Enhances polymerization of tubulin

2. Promotes microtubule assembly

3. Stabilizes microtubules against depolymerization

4. Prevents “dynamic instability”

• Causes mitotic arrest b/c anaphase cannot occur.
• ------------------------
• OTHER

• Over expression of MDR1 & Pgp170 genes → Incr
• efflux pumps → cross-resistance btwn different classes of drugs

• e.g. taxanes (paclitaxel) & vinca alkaloids
• ---------------------------------------
• ADVERSE/TOX

1. Peripheral neuropathy

2. Myelosuppression

3. Myalgias

• Pretreat w/ corticosteroids → decr severity of other S/E incl:
• --anaphylaxis,
• --peripheral edema,
• --epihora (excessive tearing),
• --erythematous pruritic maculopapular rash
• --pathologic nail changes (hypo/hyperpigmentation, oncholysis, Beau-Reil lines)

MISCELLANEOUS

CCS - S PHASE

• MOA
• 1. Inhb ribonucleotide reductase

2. Depletion of deoxynucleoside triphosphate → Prevents DNA synth

• Treats Sickle-cell disease:
• --Hydroxyurea turns on fetal Hg (HbF) gene
• --Adults prod normal HbF → fetal Hb in RBCs
• prevents sickling
• ----------------------------------
• TOX
• -MYELOSUPPRESSION

MISCELLANEOUS

• MOA
• --Hydrolyzes serum asparagine (essential amino
• acid for leukemia cells).
• --Normal cells can synth L-Asn.
• ----------------------------

• TOX
• Hepatotoxicity

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.

MISCELLANEOUS

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).

MONOCLONAL ANTIBODIES

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

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 EGFR) 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)

• G2 Synthesis of molecules needed for mitosis
• (2-10 hours)

M Mitosis (0.5-1 hour)

Anthracyclines = doxorubicin

BLEOMYCIN

CISPLATIN

CYCLOPHOSPHAMIDE

CYTARABINE

--Vincristine

--Paclitaxel

5-FU

Asparaginase

Capecitabine

B-CELL NEOPLASM

"MOPP"

Mechlorethamine

Oncovin (vincristine)

Procarbazine

Prednisone

• -------------------------
• Also ABVD:

• Adriamycin
• (doxorubicin)

Bleomycin

Vinblastine

Dacarbazine

"CHOP"

Cyclophosphamide

• Hydroxydaunorubicin
• (doxorubicin)

• Oncovin
• (vincristine

Prednisone

"CMF"

Cyclophosphamide

Methotrexate

• 5-FU
• -----------------------------

Also CAF:

Cyclophosphamide

• Adriamycin
• (doxorubicin)

5-FU

1) Mechlorethamine

2) Thiotepa

3) Cyclophosphamide

4) Melphalan

5) Chlorambucil

6) Busulfan

Carmustine (BCNU)

Lomustine (CCNU)

Also act in G0 → Tx 1o tumors of CNS

Cisplastin

Carboplatin

Procarbazine

Temozolamide

Doxorubicin aka Hydroxydaunorubicin

Idarubicin

Dactinomycin (Actinomycin D)

Mitomycin C

Topotecan

Irontecan

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
• 4) Gemcitabine
• 5) Capecitabine
• 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 specificcell 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

2. n/v w/in 30-60 min of Tx. Must pretreat w/ 5-HT3 blockers (e.g. ondasteron)

3. Teratogenic & carcinogenic (2^ leukemias): Most common cancer caused by chemo (2^ cancer) is Acute Myelogenous Leukemia (AML)

• 4. Pulmonary fibrosis (rare)
• -- Bulsulfan
• -- Chlorambucil
• -- Melphalan
• -- Nitrosureas

5. Amenorrhea & azoospermia

• 6. Hepatic venooculsive disease (HVOD or VOD): chemo obliterates branches of the small hepatic
• veins. Can → portal hypertension.

ADVERSE / TOX

• 1. Myelosuppression & immunosuppression →
• dose-limiting toxicity

2. n/v w/in 30-60 min of Tx. Must pretreat w/ 5-HT3 blockers (e.g. ondasteron)

• 3. Teratogenic & carcinogenic (2^ leukemias): Most common cancer
• caused by chemo (2^ cancer) is Acute Myelogenous Leukemia (AML)

• 4. Pulmonary fibrosis (rare)
• -- Bulsulfan
• -- Chlorambucil
• -- Melphalan
• -- Nitrosureas

5. Amenorrhea & azoospermia

• 6. Hepatic venooculsive disease (HVOD or VOD): chemo obliterates branches of the small hepatic
• veins. Can → portal hypertension.