Taxanes Vinca alkaloids Antimetabolites

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Taxane Agents

Cabazitaxel (Jevtana)
 Docetaxel (Taxotere)
 Paclitaxel (Taxol)
 Albumin-bound paclitaxel (Abraxane)
 Ixabepilone (Ixempra)

Vinca Alkaloids

 Vinorelbine
 Vincristine

Anti-mitotic Agent

Eribulin (Halaven)

Microtubules fjunction

Principle components of the mitotic spindle apparatus
 Separate the duplicate set of chromosomes during mitosis
 Function to maintain the scaffolding and shape of the cell
 Assembled by linear stacking of alternating units of alpha and beta tubulin

Tubulin polymerization function

Nucleation - elongation mechanism that allows a microtubule to shorten and elongate according the the cell cycle
Microtubules are in a constant state of motion (assembling and

Microtubule Dynamics

Treadmilling: net growth at one end of the microtubule (plus
end) and net shortening at the opposite end (minus end)
 Dynamic instability: microtubule ends switch spontaneously
between states of slow sustained growth and rapid shortening

Microtubule have 2 ends

Plus end: More rapid and polymerization
Minus end: Faster release Of subunits (depolymerization)

Taxane Agents Mechanism of Action

M phase specific,
Binds β-tubulin subunit of the microtubule and prevents disassembly (depolymerization) of the tubulin
 Results in formation of stable, nonfunctional microtubules
 Cell is unable to complete cell division and undergoes

Paclitaxel (Taxol) Uses

Majority of solid tumors
 Breast, Lung, Ovarian,
Testicular, Head and Neck,
among others

Paclitaxel (Taxol) Toxicities

Neutropenia (DLT)
 Nausea / Vomiting
 Peripheral neuropathy
 Alopecia
 Arthralgia / Myalgia
 Anaphylactic
hypersensitivity (due to
 Flushing / Rash
 Cardiac arrhythmias

Paclitaxel (Taxol) Dose Adjustment

Hepatic dysfunction
 Hepatic metabolism
through CYP 2C8

Paclitaxel (Taxol) Special Compounding

Drug is diluted in 50/50
Cremaphor (castor oil) and
 Plasticizer DHEP leaches
into solution = Toxic

Paclitaxel (Taxol) Premedications
(30 minutes prior)

Histamine-2 receptor
 Famotidine 20mg IV
 Diphenhydramine 25 mg
 3 doses of dexamethasone:
12 - 20 mg PO at 12, 6 and
1 hour prior to paclitaxel
 Antiemetics

Albumin-Bound Paclitaxel (Abraxane)

Indicated only in metastatic breast cancer following
progression of an anthracycline-based therapy
 Similar toxicities to paclitaxel
 LOWER risk of hypersensitivity reaction
 HIGHER rate of peripheral neuropathy and neutropenia
 Dosing adjustments for hepatic dysfunction

Docetaxel (Taxotere) Uses

Solid tumors primarily
 Prostate, Breast, Lung,
Ovarian, Bladder, Head
and Neck

Docetaxel (Taxotere) Toxicities

Neutropenia (DLT)
 Peripheral neuropathy
 Alopecia
 Fluid retention
 Anaphylactic
hypersensitivity (due
toTween 80)
 Arthralgia / Myalgia
 Nausea / Vomiting
 Flushing / Rash

Docetaxel (Taxotere) Dose Adjustment

Hepatic dysfunction
 Hepatic metabolism through
CYP 3A4/5*

Docetaxel (Taxotere) Special Compounding

Drug is diluted in Polysorbate
80 and alcohol
 Plasticizer DHEP leaches into
solution = Toxic

Docetaxel (Taxotere) Premedications (30 minutes prior)

Diphenhydramine 25 mg
 Dexamethasone 8mg PO BID
beginning day before
docetaxel and continuing for
3 days (reduces edema)
 Antiemetics

Ixabepilone (Ixempra) approved for

Only approved for use in breast cancer after failure of
anthracyclines, taxanes and capecitabine

Ixabepilone (Ixempra) Toxicities

Peripheral neuropathy (DLT)
 Neutropenia
 Myocardial ischemia
 Myalgia
 Fatigue
 Nausea
 Anaphylactic hypersensitivity
(contains Cremaphor*)
 Premedicate like paclitaxel

Ixabepilone (Ixempra) dosing limitations

Dose reduce in hepatic dysfunction

Ixabepilone (Ixempra) Epithilone Drug Class MOA:

Binds to beta-tubulin (occupies different binding site than taxanes)
 5 - 25x more potent than

Eribulin (Halaven) MOA

non-taxane microtubule inhibitor, halichondrin B analog which inhibits growth phase of microtubules by inhibiting formation of
mitotic spindle

Eribulin (Halaven) Uses

Metastatic breast cancer

Eribulin (Halaven) Toxicities

 Neutropenia
 Anemia
 QTc prolongation
 Peripheral neuropathy
 Alopecia

Cabazitaxel (Jevtana) Uses

Hormone refractory metastatic prostate cancer

Cabazitaxel (Jevtana) Toxicities

 Neuropathy
 Hypersensitivity reaction
(contains polysorbate 80)
 Premediate like paclitaxel
 Nausea / vomiting /
 Arthralgia
 Alopecia

Vinca Alkaloids MOA

Inhibit tubulin polymerization  Block ability to form a
mitotic spindle
 Cell is unable to complete cell division and undergoes

Taxanes Vinca alkaloids MOA diagram

Vincristine (Oncovin) Uses

Leukemia, Lymphoma

Vincristine (Oncovin) Toxicities

Peripheral neuropathy
 Paralytic ileus
 Prophylactic stool
 2 tabs QHS - titrate to regulate bowel movements
 Minimal nausea
MAX dose = 2 mg  Vesicant

Vincristine (Oncovin) dose adjustments

 Hepatic
 Requires dosing
adjustment for hepatic

Vinblastine (Velban) Uses

Lymphoma, melanoma

Vinblastine (Velban) Toxicities

Neutropenia (DLT)
 Thrombocytopenia
 Alopecia
 Mild peripheral neuropathy
 Minimal nausea
 Vesicant

Vinblastine (Velban) dose adjustments

Requires dosing adjustment for hepatic insufficiency

Compounding Vinca Alklaloids

FATAL if given by intraTHECAL route
 Slow, painful death from myeloencephalopathy
 Ascending motor and sensory neuropathy
 World Health Organization recommends compounding these
drugs in a piggyback
 NO Syringes = NO confusion for intrathecal administration

"S" Phase Agents Antimetabolites

Fluouracil / Capecitabine

Antifolate Drugs

Methotrexate and Pemetrexed

S Phase Specific Activity antifolate Deficiency

impairs thymidylate and purine synthesis (DNA synthesis)
 Megaloblastic anemia

Methotrexate (Trexall) Uses

Leukemia, Lymphoma
 Various solid tumors
(sarcoma, breast, head and
neck, choriocarcinoma)
 Non-oncology
 Psoriasis, rheumatoid arthritis,
Crohn's disease, graft versus
host therapy, abortifacient

Methotrexate (Trexall) MOA

Inhibits the enzyme dihydrofolate reductase
 DHFR replenishing cell's tetrahydrofolate supply
 Increasing levels of dihydrofolate inhibits activity of thymidylate synthase
 Blockade of DHFR = inhibition of thymidylate and purine

Methotrexate (Trexall) Special Notes

Wide variability in dosing!
 2.5 mg once a week - 20 grams once a month
 PO, IV, can give intrathecally
 Eliminated in urine -adjust dose for renal dysfunction
 High protein binding
 3rd space fluid collection (pleural effusions, ascites)

Methotrexate (Trexall) Toxicities

 Myelosuppression (neutropenia, thrombocytopenia)
 Renal toxicity
 Pneumonitis
 Alopecia
 Infertility

High-Dose Methotrexate can

High - dose methotrexate, Requires urine alkalinization (pH >
7.5), Requires high volume hydration (250 ml/m2/hr) for renal
protection, Requires leucovorin rescue which will rescue both healthy and malignant cells

High-Dose Methotrexate Leucovorin rescue

Initiated > 24 hours after the dose of methotrexate
 20 mg IV/PO Q6H
 Increase dose based on algorithm
 Treat with leucovorin until methotrexate level < 1 x 10 -7 molar

Mucositis Tx

Supportive Care
 IV/PO pain medication
 Saliva substitute
 Soft tooth brush and baking soda water rinse
 Cryotherapy
 "Magic Mouth Wash"
 Hydrocortisone 110 mg IV, Diphenhydramine elixer 120 mL, Nystatin
suspension 120 mL (may substitute Maalox, tetracycline, sucralfate)
 5 - 10 mL PO Q4H prn pain
 +/- viscous lidocaine 2% (beware of cardiac adverse effects)

Pemetrexed (Alimta) Uses

Non-small cell lung cancer, drug of choice for mesothelioma

Pemetrexed (Alimta) MOA

 Inhibits thymidylate synthase
 Weakly inhibits DHFR
 Inhbitis GARFT (glycinamide ribonucleotide formyltransferase) - enzyme necessary for purine synthesis

Pemetrexed (Alimta) Toxicities and Supportive Care

 At least 7 days prior to 1st dose:
 Cyanocobalamin 1000 mcg IM then every 9 weeks
 Folic acid 1 mg PO daily
 Pruritic rash (40%)
 Dexamethasone 4 mg BID day -1, day 0 and day +1 t
 Prevention of rash

Antifolate mechanism of action

Fluouracil (5-FU, Adrucil) is

Fluorinated analog of naturally occurring pyrimidine of uracil that is S-phase specific

Fluouracil (5-FU, Adrucil) MOA

Monophosphate form of 5-FU (F-dUMP) inhibits thymidylate
 Competes with natural substrate, dUMP for
thymidylate synthase binding
 dUMP required to make thymidine (building block of DNA)
 Triphosphate form of 5-FU (FUTP) incorporates into RNA as
a false base pair

5-FU drug Interactions

 Addition of folates during 5-FU infusion increases the stability of the 5-FU monophosphate - thymidine sythase bond
 Results in increased
cytotoxic activity
 Increased PT/INR
 Increased phenytoin levels
 Radio-sensitizer

Fluoruracil Uses

Breast, Colorectal, Gastric, Esophageal, Head and Neck, Pancreatic, Cervical Cancer

Fluoruracil Toxicity

 Mucositis
 Diarrhea
 Palmar-Plantar erythema (Hand-Foot Syndrome)
 Photosensitivity
 Mild Nausea
 Neurotoxicity

Capecitabine (Xeloda) FDA indicated

Colorectal Cancer (CRC)
 Single agent for adjuvant therapy after complete tumor
 Single agent, first line therapy in metastatic CRC

Metastatic Breast Cancer
 Single agent
 In combination with docetaxel or lapatinib

Antipyrimidine Antimetabolites Cytidine Analogues


Cytarabine (Ara-C) Uses

Leukemia and Lymphoma
 No activity in solid tumors

Cytarabine (Ara-C) Elimination

Enzyme cytidine deaminase
deactivates Ara-C
 Enzyme present in low levels in
the CNS
 Effective for intrathecal
 Dose adjust for renal dysfunction
(increased neurotoxicity)

Cytarabine (Ara-C) MOA

Analog of deoxycytidine
 Incorporates into DNA
 Terminates chain elongation
 Inhibits DNA polymerase
 Cytarabine is phosphorylated to an active triphosphate form (aca-CTP) within tumor cells

Cytarabine (Ara-C) Adverse Effects

 Conjunctivitis
 Nausea / Vomiting
 Skin rash (palmar-plantar)
 Cerebellar toxicity
 LFT elevation (transient)
 Diarrhea

Gemcitabine (Gemzar) Uses

Bladder, Pancreatic, Lung, Breast,
Ovarian Cancer
 Radiation sensitizer

Gemcitabine (Gemzar) Toxicities

 Acute respiratory distress syndrome
 Rash
 Nausea / Vomiting
 Thrombocytopenia - DLT
 Flu-like symptoms
 Transient elevation in LFTs

Gemcitabine (Gemzar) MOA

Analog of deoxycytidine
 Incorporates into DNA
 Terminates chain elongation
 Competes with the natural substrate, dCTP (deoxycytidine triphosphate), for DNA incorporation
 Inhibits DNA polymerase
 Inhibits DNA synthesis
 Inhibiting an enzyme responsible for the production of deoxynucleotides, ribonucleotide reductase

Azacytidine (Vidaza) & Decitabine (Dacogen) Uses and MOA

Myelodysplastic syndrome
Acute myeloid leukemia
 Limited activity

Hypomethylating agents
Incorporated into DNA and RNA

Azacytidine (Vidaza) & Decitabine (Dacogen) Elimination

Enzyme cytidine deaminase
deactivates Ara-C

Purine Antimetabolites Guanine Analogs

6-mercaptopurine (6-MP,Purinthol)
6-Thioguanine (6-TG)
Azothioprine (Imuran)

Purine Antimetabolites Adenosine Analogs

Cladribine (2-cda, Leustatin)
Fludarabine (Fludara)

Guanine Analogs (6-MP, 6-TG) MOA and Uses

Converted to ribonucleotides that are incorporated into DNA
 Inhibit purine synthesis

Uses: Leukemia

Guanine Analogs (6-MP, 6-TG)

Allopurinol increases 6-MP toxicity
 6-MP is metabolized by xanthine oxidase
 Allopurinol is a xanthine oxidase inhibitor

Adenosine Analogs Fludarabine Cladribine & Pentostatin Uses


Adenosine Analogs Fludarabine MOA

Inhibits DNA polymerase and ribonucleotide reductase,
incorporated into DNA

Cladribine & Pentostatin Adenosine Analogs MOA

Inhibits ribonucleotide reductase
 Unlike fludarabine, these drugs are not deactivated by adenosine deaminase (cladribine inhibits AD)

Adenosine Analogs Fludarabine Cladribine & Pentostatin cause

DLT - myelosuppression (T cell depression)
 Risk of opportunistic infections of PCP, HSV
 *Recommend anti-infective prophylaxis*

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