Chemo Agents 2 Natural Products and Derivatives

nature

is a rich source of anticancer drugs with abundant pool of diverse chemicals and pharmacologically active compounds

Anthracyclines

-Isolated from Streptomyces species.

• Doxorubicin (DOX)

• Daunorubicin (DNR)

• Epirubicin (EPI)

• Idarubicin (IDA)

-All 4 structures are identical with exception of small changes in colors

-Inhibit Topoisomerase II Class of enzymes

Doxorubicin (ADRIAMYCIN)

-One of the most widely used anticancer agents; broad- spectrum agent.

-Cause apoptosis of cancer cells by a complex network of events which include but not limited to:

o Intercalation into DNA

o Generation of reactive oxygen species (ROS)

o Topoisomerase II inhibition

-Color of drug in...and out..is blood red— "Red Devil"

-Severe local tissue necrosis will occur if there is extravasation during administration (DO NOT give IM or SubQ)

cardiotoxicity of Doxorubicin

• Characterized by a dose-dependent decline in mitochondrial oxidative phosphorylation.

• Reactive oxygen species, generated by the interaction of doxorubicin with iron, can then damage cardiomyocytes (heart cells).

• Inhibition of Topoisomerase 2β, which is active in quiescent non-proliferating cells including cardiomyocytes, is now thought to be the key mediator of anthracycline-induced cardiotoxicity.

• Reversible damage with low dose; high dose can lead to irreversible heart damage—even years later.

• Lifetime maximum cumulative dose of DOX should not exceed 550 mg/m2

mitigation of anthracycline mediated cardiotox

-Reduce dose when appropriate.

-If patient cumulative dose DOX > 300 mg/m2, administer dexrazoxane (ZINECARD, DRZ)

dexrazoxane (ZINECARD, DRZ) MOA

-Chelates iron and blocks iron-mediated free radical generation in anthracycline-induced cardiomyopathy.

-Out-competes anthracyclines for inhibition of topoisomerase IIβ, which is constitutively expressed in cardiomyocytes

Doxorubicin liposomes (DOXIL)

-is a reformulated version of doxorubicin. DOXIL takes the active agentdoxorubicin and places it into a fat bubble called a liposome (Stealth liposomes)and another layer of PEG

-coating allows DOXIL to evade detection and destruction by the immunesystem, which increases the time the drug is in the body (increase drugexposure)

-The majority of the drug stays inside the liposome while in the blood (at least90%). Therefore, DOXIL has more time to reach the tumor tissue, where themedication slowly diffuses out.

-Administered by IV infusion for a variety of cancer indications.

-But...same black box warnings for cardiotoxicity and maximal dosages.

Bleomycins

-are a family of glycopeptide antibiotics from Streptomyces with profound antitumor activity

-Indicated for squamous cell carcinomas, testicular carcinoma, and Hodgkin's Lymphoma (ABVD regimen)

-Consist of a metal binding, DNA binding, and carbohydrate domain

Bleomycins MOA

-bind metals -Fe(II) or Cu(I) and oxygen and can catalyze formation of single-stranded (ss) and double-stranded (ds) DNA breaks.

-The damage is similar to that generated by ionizing radiation

bleomycin pulmonary toxicity (BPT)

What is the most severe adverse event that is dose dependent and involves lung inflammation that often progresses to lung fibrosis?

Topoisomerase

• Enzyme that works in front of replication fork.

•Introduces nicks in the DNA backbone allowing the rotation of one strand around the other. This releases the torsional strain which otherwise accumulates in front of the advancing replication fork

Topoisomerase Inhibitors

prevent this process; several FDA approved anticancer drugs are classified as topo inhibitors

CAMPTOSAR (Ironotecan)

-Topoisomerase I Inhibitor: Prodrug indicated for metastatic colorectal cancer, 1st line used with 5-Fluorouracil (F-FU) and leucovorin.

-S-phase specific

• Binding of irinotecan prevents topoisomerase I-mediated re-ligation of the DNA resulting in double-strand breaks in DNA and subsequent induction of apoptosis (programmed cell death).

prodrug

Irinotecan is a _________

active

SN-38 is the ______ metabolite of Irinotecan.

Irinotecan

-Dose related adverse events are reversible, not cumulative

-BLACK BOX

• Diarrhea (SEVERE)

• Myleosuppression (SEVERE)

-These adverse events are correlated with high exposure of SN-38—and defects in UGT1A1

• Non-functional UGT1A1 alters metabolism of SN-38--- simulated overdose.

• Problem with homozygous *28 allele

Podophyllotoxins

• Etoposide and teniposide are Topo-II inhibitors and synthetic derivatives of the natural product podophyllotoxin (an anti-tubulin drug!).

• This is a good example where modifying the structure of a drug may change its molecular target.

• Indicated for testicular cancer and many others

Microtubules (MT)

-are cell structures made of α- and β-tubulin subunits, and the form hollow, cylindrical structures

-play a key role in cell machinery, cell growth and division and motility

-generate the mitotic spindle, a very important structure needed by eukaryotic cells to segregate their chromosomes correctly during cell division

MT dynamic equilibrium

is characterized by binding of tubulin dimers to a growing MT and subsequentde-polymerization back to tubulin dimers. GTP dependent.

Oncovin and Velban

What are the complex natural products from periwinkle?

-Vincristine (ONCOVIN)

• Vincristine sulfate liposome injection (MARQIBO)

-Vinblastine (VELBAN)

-The Vinca alkaloids arrest the cell cycle in metaphase by a fast and reversible binding to the β-tubulin subunit in a region called the Vinca domain.

-Prevent assembly into microtubules, thus are termed microtubule destabilizers.

-Vincristine is combined with other drugs to treat acute lymphoblastic leukemia (ALL) and in Hodgkin's and non-Hodgkins lymphomas

Vincristine sulfate liposome injection (MARQIBO)

• Nanoparticle-Encapsulated formulation: Optisome Technology

• Enhanced Efficacy-Reduced Toxicity

• Indicated for ALL (Philadelphia Chromosome Negative)

• IV administration only; MARQIBO has different dosage recommendations than vincristine sulfate injection. Verify drug name and dose prior to preparation and administration to avoid overdose.

Taxanes and Epothilones

What are the 2 major classes of microtubulin stabilizers?

Taxanes

-Paclitaxel (TAXOL)

• Paclitaxel-albumin formulation (ABRAXANE)

-Docetaxel (TAXOTERE)

-Cabazitaxel (JEVTANA)

Epothilones

Ixabepilone (IXEMPRA)

Paclitaxel

-first in class MT stabilizer

-rich hx associated with this drug class

-taxanes bind to a pocket in beta-tubulin-prevents depolymerization of microtubules

Taxanes class

• TAXOL (paclitaxel)

• TAXOTERE (docetaxel)

• JEVTANA (cabazitaxel)

• Taxanes form the backbone of chemotherapeutic regimens in breast, ovarian, non-small cell lung, and head and neck cancers.

• Major toxicities, including hypersensitivity reactions, myelosuppression, and peripheral neuropathy, often limit the use of taxanes.

• Often the side effects are increased when these drugs are prescribed in combination with other medicines like platinum agents and doxorubicin.

issues with FDA approved taxanes

• Low aqueous solubility and need for solubilization vehicles, Cremophor® EL (polyoxyethylated castor oil)

• Hypersensitivity issues

• Resistance; taxanes efluxed by P-gp pumps

• Low plasma half life

• Administered by IV infusion—like most other chemotherapies

ABRAXANE (Nab-paclitaxel)

-uses albumin, a human protein, to deliver the chemotherapy. Itdoes not contain emulsifiers, like Cremophor. It is a small advance intaxane-based chemotherapy

-eliminates the need for premedication with steroids or antihistamines for hypersensitivity reactions caused by these emulsifiers. Plus ABRAXANE is administered in just 30 minutes (compared to 3 hours for solvent-based paclitaxel)

-Indicated for :Metastatic breast cancer, Metastatic pancreatic cancer, and Metastatic NCSLC

Paclitaxel AEs

bradycardia, alopecia, nail discoloration-dermatological effects

Docetaxel AEs

fluid retention, skin toxicities, and stomatitis

Cabazitaxel AEs

infections, nausea, vomiting, diarrhea, and constipation

Nab-paclitaxel AEs

nausea and vomiting, alopecia, myalgia, and elevation of liver enzymes

Ixabepilone (IXEMPRA)

-Epothilones are 16-membered macrocyclic lactone natural products isolated from myxobacterium species

-is a natural product derivative ofepothiolne B.

-These act through the same mechanism of action aspaclitaxel, by stabilizing microtubules and inducing apoptosis

used:

• in combination with capecitabine is indicated for the treatment of metastatic or locally advanced breast cancer in patients after failure of an anthracycline and a taxane .

• as monotherapy is indicated for the treatment of metastatic or locally advanced breast cancer in patients after failure of an anthracycline, a taxane, and capecitabine

possesses low susceptibility to tumor resistance mechanisms including efflux transporters, such as MRP-1 and P-glycoprotein (P-gp)

What is the benefit of Ixabepilone (IXEMPRA) over taxanes?