Oncology Exam #2

• Plant-derived alkaloid indigenous to: Eastern Asia/China, Japan, and India
• The bark of Cephalotaxus harringtonia var. drupacea (Sieb & Zucc.)
• Natural homoharringtonine is extracted from the bark of Cephalotaxus sp.
• Semi-synthetic homoharringtonine is known as Omacetaxine Mepesuccinate
• Common names include: Plum Yew, Japanese Plum Yew, Harrington Plum Yew, and Cow Tail Pine

• Tertiary amine
• Cephalotaxine derivative in which the secondary alcohol group has been esterified with different naturally occurringacids
• Homoharringtonine is a homologue (one additional methylene function in esterchain) of harringtonine

• Induces apoptosis (programmed celldeath) in myeloid cells via inhibition of protein synthesis
• Inhibits angiogenesis
• Occurs as a result of reversible inhibition of ribosome/elongation factor complex
• Acts independently of tyrosine kinase inhibitors

Potentially in CML, AML and MDS (myelodysplastic syndrome [increased risk to transformation to AML]

Phase 3 studies in CML

Nonhematologic toxicities were infrequently observed

Synthetic macrocyclic ketone analog of halichondrin B, a large macrocyclic polyether first isolated from the sponge Halichondria okadai in 1986

**Halichondrin B was highly cytotoxic in murine leukemia cells**

• Macrocyclic polyether
• Consists of “right-hand portion” of Halichondrin B structure
• Acetate, malonate, methylmalonate metabolites

• Tubulin depolymerizer
• Disrupts polymerization of themicrotubules necessary in mitosis
• Binds near the Vinca domain

Advanced, “heavily-treated”, metastatic breast carcinoma

November 15, 2010 – FDA approves for thetreatment of patients with metastaticbreast cancer who have received at leasttwo prior chemotherapy regimens for latestagedisease

HALICHONDRIN B

Mixture of cytotoxic glycopeptide antibiotics isolated as their water soluble sulfate salts from cultures of a strain of Streptomyces verticillus

• Isolated as a blue-colored Cu(II) coordinated complex
• The Cu+2 is removed prior to marketing via catalytic reduction
• Increases cost but frees up critical functional groups for chelation with intracellular Fe+2
• Bleomycin complexes (chelates) in vitro with divalent and trivalent cations

• Contains an iron-binding region and aDNA-binding region at opposite ends of the molecule
• Iron is a mandatory co-factor for free radical generation and resulting cytotoxicity of bleomycin
• Cytotoxicity results from activated oxygenfree radical species which produce single- and double-strand DNA breaks

• Hodgkin’s and Non-Hodgkin’s lymphomas
• Germ cell tumors
• Head and neck squamous cell carcinoma
• Skin, cervix, vulvar squamous cell carcinoma

• Pulmonary Toxicity (most severe toxicity): Pneumonitis & Pulmonary Fibrosis
• Dermatologic Rxns: desquamation, rash, hyperpigmentation, hyperkeratosis

Major antibiotic of a mixture ofactinomycins produced by strains of Streptomyces parvulus

• Heteroaromatic chromopeptide
• Planar phenoxazone chromophore

• Preferentially binds to guanine-cytosinebase pairs
• Binds to single- & double-stranded DNA as an intercalator with formation of toxic oxygen free radicals that promote strand breaks

• Wilms’ tumor
• Rhabdomyosarcoma
• Choriocarcinoma
• Ewing’s sarcoma

• Dermatological: hyperpigmentation & extravasation
• Red-orange color of bodily fluids

First isolated from cultures of Chromobacterium violaceum by Fujisawa Pharm. in 1990

• Depsipeptide: A peptide having both amide and ester bonds
• Bicyclic peptide consisting of 4 amino acid residues and a novel acid

Histone deacetylase inhibitor (HDI)

HDIs possess anti-tumor activity: Regulate gene transcription or translation; Induce cell cycle arrest and apoptosis through histone hyperacetylation

• Cutaneous T-cell Lymphoma (CTCL)
• Peripheral T-cell Lymphoma (CTCL)

• Asthenia (weakness)
• ECG changes -- requires periodic monitoring of ECG and serum electrolytes

One member of a group of antitumor antibiotics isolated from cultures of Streptomyces caespitosus

• Mitosanes (1,2-disubstituted indoloquinones)
• Pyrrolo [1,2-a] indole nucleus
• Contains quinone, aziridine, and carbamate functions
• Only compound in nature to contain an aziridine ring
• Water soluble, Blue-violet colored solution
• Unstable in both acidic and alkaline media
• Limited stability of reconstituted solutions

INHIBITS TRANSCRIPTION BY TARGETING DNA-DEPENDENT RNA POLYMERASE

• Disseminated adenocarcinoma of the stomach and pancreas
• Unlabeled used: Superficial bladder cancer; Adjunct to surgical excision in primary or recurrent pterygia (web-like superficial growth on the subconjunctiva)

• Dose-related Hemolytic-uremic syndrome
• Dermatologic Rxns
• Interstitial pneumonitis

• Synthetic indoloquinone
• Analog of mitomycin C

Mitomycin C

• Bioreductive prodrug
• Intracellular reductases catalyze the conversion to active metabolites in hypoxic cells
• Active metabolites alkylate DNA producing apoptotic cell death

Therapy of non-muscle invasive (superficial) bladder cancer via intravesical instillation following transurethral resection (TUR) of bladder tumor

Fermentation product of Streptomyces achromogenes

• Pale gold water soluble nitrosourea
• 2-Deoxy-2-(3-methyl-3-nitrosoureido)-Dglucopyranose
• Mixture of alpha and beta anomers, with solutions undergoing mutarotation

Decomposes to form carbonium ions that are electrophilic and can alkylate or carbamoylate various purines or pyrimadines to form adducts involved in inter- or intrastrand DNA cross-linking

Also, methylates guanine at the O-6 position and irreversibly inactivates DNA-repair enzyme, mammalian alkyl transferase

Metastatic islet pancreatic carcinoma

• Very severe nausea and vomiting
• Nephrotoxicity
• Myelotoxicity is rare

First isolated from cultures of Streptomyces peucetius var. caesius

• Cytotoxic glycosidic anthracycline
• Part of the rhodomycin group of compounds
• Today is prepared via semi-synthesis from daunorubicin
• Planar anthraquinone nucleus linked glycosidically to an aminosugar (daunosamine)

Doxorubicin

• Intercalates between base pairs in DNA double helix, affecting DNA and RNA synthesis
• Generates reactive oxygen intermediates and free radicals
• Inhibits Topoisomerase-II

• Acute lymphoblastic leukemia (ALL)
• Hodgkin’s and non-Hodgkin’s lymphomas
• Carcinomas: Breast, Ovarian, Bladder
• Sarcomas: Kaposi’s sarcoma (AIDS-related)

• Cardiovascular (both acute and chronic): Arrhythmias & CHF
• Discoloration of body fluids: Urine turns Red-to-orange
• Strong vesicant

• S-(+)- isomer of razoxane
• A diamine and a di-imide
• A cyclic derivative of EDTA

A cardioprotective intracellular chelating agent that reduces (or prevents) the incidence and severity of cardiotoxicity associated with anthracycline-derived antitumor agents

• Semisynthetic analog of doxorubicin
• Water soluble HCl salt is employed

• C-4’ epimer of doxorubicin
• Same physical/chemical properties as doxorubicin
• Red-orange color

Same as Doxorubicin: inhibits topoisomerase-II

• Adjuvant for early stage breast cancer that has spread to the regional (axillary) lymph nodes but has been treated surgically with removal of all known tumor
• Metastatic breast carcinoma
• Gastric carcinoma

Same as Doxorubicin (cardiotoxicity & discoloration of bodily fluids) with slightly less cardiotoxicity

• Originally isolated from cultures of Streptomyces peucetius var. caesius
• Also obtained from cultures of Streptomyces coeruleorubidus

• A C-8 deoxy-doxorubicin derivative
• Same physical and chemical properties as doxorubicin
• Red-orange color
• Water soluble HCl salt used

same as doxorubicin: inhibits Topoisomerase-II

• Acute leukemias (lymphoblastic andmyelogenous)
• Kaposi’s Sarcoma (AIDS-related)

Same as Doxorubicin: Cardiotoxicity and bodily-fluid discoloration

• Synthetic analog of daunorubicin
• 1-Demethoxydaunorubicin ---- Demethoxylation flattens the aromatic ring facilitating intercalation between base pairs
• High degree of lipophilicity affords increased rate of cellular uptake
• Same phys/chem properties as doxorubicin

• Same as doxorubicin: inhibits topoisomerase-II
• Partially overcomes MDR

• Acute leukemias (AML, ALL)
• Chronic leukemia (CML) in blast crisis

Same as Doxorubicin: cardiotoxicity and bodily-fluid discoloration

• Semisynthetic analog of doxorubicin
• Valeric acid ester of the N-trifluoroacetylamide of doxorubicin ---- Basic amine nitrogen of doxorubicin is lost, and replaced with neutral amidic nitrogen; Water solubility is low
• High degree of lipophilicity affords increased rate of cellular uptake
• Supplied in Cremophor EL/Dehydrated Alcohol mixture as a solution

Same as Doxorubicin: inhibits topoisomerase II (but is less bound to DNA)

Intravesical therapy of BCG-refractory carcinoma in situ (CIS) of the urinary bladder in patients who would be poor candidates for immediate cystectomy

• Local reactions: Irritation, Urgency, Frequency, Dysuria
• Systemic reactions are uncommon as total recovery of voided anthracyclines is 99%,with systemic exposure being negligible

A C-1 demethoxy-doxorubicin disaccharide

• Same as Doxorubicin: More marked topoisomerase II mediated cleavage
• Significant activity against a number of tumors

an analog of ametantrone

• A dihydroxyametantrone
• Blue-black solid
• Forms water soluble HCl salt
• Not glycosylated (as doxorubicin family)
• Amphoteric

Same as Doxorubicin: inhibits Topoisomerase II

• Acute myelogenous leukemia (AML)
• Advanced hormone-refractory prostatecancer
• Non-Hodgkin’s lymphoma
• Reduction of neurologic disability orfrequency of relapses in multiple sclerosis(MS) patients (uncommon application)

Same as Doxorubicin: Cardiotoxicity (CHF)

• A synthetic aza-anthracenedione
• Discovered in a search for novel heteroanalogs of anthracenediones

• Blue solid
• Forms water soluble HCl salt
• Pixantrone = pyridine
• Not glycosylated (as doxorubicin family)

A novel major groove binder

Relapsed or refractory Non-Hodgkins lymphoma

• MINIMAL CARDIOTOXICITY
• Incidence of severe adverse effects was similar between the drug and the control arm