Oncology Exam 3

A semisynthetic derivative of sirolimus (rapamycin)

Macrolide (macrocyclic lactone) skeleton
Rapamycin derivative: 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate] rapamycin
Colorless solid
No ionizable functional groups
Water insoluble

An inhibitor of the enzyme mTOR (mammalian Target Of Rapamycin – a keyregulatory kinase)
Binds to an intracellular protein (FKBP-12)
This protein-drug complex inhibits the activity of mTOR that controls cell division
Inhibition of mTOR activity resulted in a G1growth arrest in treated tumor cells

Renal Cell Carcinoma

Hyperlipidemia and hyperglycemia

Macrolide (macrocyclic lactone) skeleton
A semi-synthetic derivative of Rapamycin (Sirolimus): 42-O-(2-hydroxy)ethyl rapamycin
Colorless solid
No ionizable functional groups
Water insoluble

Renal Cell Carcinoma
Pancreatic Neuroendocrine Tumors (unresectable, locally advanced or metastatic disease)

subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosisin patients who require therapy but are not candidates for surgical resection

These two drugs do not have any special adverse effects detailed

Macrolide (macrocyclic lactone) skeleton
A semi-synthetic derivative of Rapamycin (Sirolimus): 42-O-dimethylphosphinate rapamycin
Colorless solid
No ionizable functional groups
Water insoluble

In Phase 3 clinical trials for the therapy ofmetastatic soft-tissue and bone sarcomas that are responsive to chemotherapy

In Phase 2 clinical trials ongoing for advanced endometrial cancer, prostate cancer and non-small cell lung cancer

A semisynthetic derivative of thepolyketide macrolactone (macrolide)Epothilone B

The first of the epothilones, a new class ofcytotoxic compounds

macrolactam derivative of the macrolactone Epothilone B

No readily ionizable functional groups; Lactam N atom is neutral; Thiazole N atom electrons are delocalized in ring current and unavailable for salt formation

Solubility is achieved via incorporation into solution in a mixture of Polyoxyethylated castor oil (52.8%) & Dehydrated alcohol (39.8%)

MOA similar to the taxanes: Bind directly to the αβ-tubulin heterodimersubunit on microtubules. Once bound, the rate of heterodimeric tubulin dissociation decreases ->-> stabilizes the microtubules ->-> inhibits microtubule depolymerization

Acts as an antimitotic - blocks the metaphase -> anaphase step in mitosis which leads to apoptosis

Binds in a unique manner to β-tubulin and appears to be active against taxane-resistant tumor cell lines

Combination with Capecitabine (Xeloda®) in the therapy of metastatic or locally advanced breast cancer patients after failure of an anthracycline and a taxane

Monotherapy of metastatic or locally advanced breast cancer in patients after failure of an anthracycline, a taxane, and capecitabine

Causes peripheral neuropathies, mainly sensory (20%)

identified from Micromonospora echinospora ssp. calichensis

Culture of Micromonospora echinospora ssp. calichensis yielded a number of metabolites, the most important being this compound

This compound was an extremely cytotoxic substance that became the lead compound in the emerging novel family of enediynes

Binds to DNA in the minor groove resulting in: Double-strand breaks, Inhibition of DNA synthesis and function & Cell death

This drug is covalently linked to a recombinant humanized monoclonal antibody (Gemtuzumab ozogamicin) directed against the 67 kDa cellsurface glycoprotein CD33

Relapsed CD_33⁺ AML in patients in first relapse who are 60 years or older AND who are not considered for cytotoxic chemotherapy

Infusion-related events: Hypotension and severe allergic reactions

Premedicate with acetaminophen + diphenhydramine (and sometimes methylprednisolone)

A chemically modified tetracycline: 4-dedimethylamino, 6-demethyl-6-deoxytetracycline

Clinical evaluations ongoing in patients with: Kaposi’s sarcoma, Rosacea, Acne & Acute respiratory distress syndrome

A plant commonly known as Mayapple or American Mandrake

Lignan (dimeric phenylpropanoid)

Biological activity is dependent upon the lactone ring existing in the trans-configuration

INHIBIT MICROTUBULE FUNCTION; BINDS TO TUBULIN AND ARRESTS MITOSIS IN METAPHASE - ANTIMITOTIC

Topical therapy of: Anogenital warts due to papillomavirus or condyloma acuminata warts

Semi-synthetic lignan derivative of podophyllotoxin

Phosphate ester is useful in high-dose chemotherapy regimens ---- Lessens volume of solution administered & Lessens time of administration

COMPLEXES WITH TOPOISOMERASE II TO PRODUCE DOUBLE-STRANDED DNA BREAKS; ANTIMITOTIC - G2

Refractory testicular tumors (germ cell tumors)
Small cell and non-small cell lung cancer
Hodgkin’s and non-Hodgkin’s lymphomas

Special AEs not documented ---- Increased risk of secondary malignancies, typically developing within 5-8 years

Semi-synthetic lignan derivative of podophyllotoxin

MOA is the same as etoposide

Refractory acute leukemia (ALL)

Semi-synthetic lignan derivative of podophyllotoxin that does not have any special adverse effects

Source is the fruits of Ammi visnaga Lam.(Apiaceae), a Mediterranean herb

A furanocoumarin
Pale yellow color
Low water solubility

Noncancer-related applications include:
– Severe idiopathic vitiligo (acquiredleukoderma): Vitiligo
– Enhance tolerance to sunlight in blond persons with fair complexations who suffer “sun allergy” (severe sunburns)
– Severe, recalcitrant, disabling psoriasis

Cancer-related applications include:
–Cutaneous T-cell Lymphoma (CTCL)(Mycosis fungoides)
–Cervical dysplasia: Application of psoralen-containing gel in photodynamic therapy; Limits need for surgical treatment

INTERCALATES WITH DNA FORMING ADDUCTS (WHEN LIGHT ACTIVATED, ACTS AS ALKYLATING AGENT)

SEVERE BURNS AND BLISTERING IFTHERE IS POST-PUVA LIGHT EXPOSURETOO SOON AFTER THERAPY

Isolated from the Seeds of the plant Euphorbia lathyris (Fam.Euphorbiaceae) or the Sap of the plant Euphorbia peplus (Fam.Euphorbiaceae)

Diterpene alcohol (4 x C5 units) that is alsoa tetraol

Activates protein kinase isoforms, inducing apoptosis

Applied as a gel in the short-course topical therapy of actinic keratosis and non-melanoma skin cancers – Phase 3

Great benefit in treating actinic keratosis before this lesion progresses to invasive squamous carcinoma

Physiological metabolite of retinol

Prepared by oxidation of retinal

Carotene derivative

Lipophilic, with low water solubility

MOA is unknown; Not cytolytic

Induces the maturation of acute promyelocytic leukemia cells in culture

Induction of remission (ONLY) in patients with acute promyelocytic leukemia (APL)(Classification M3 [genetic]) who:
- Are refractory or have relapsed from anthracycline (doxorubicin family) therapy
- Anthracycline-based therapy is contraindicated

Effects commonly associated with highdoses of Vitamin A (nearly universal): Headache, fever, dryness of skin and mucous membranes

Serious/grave (25-40%): Rapid leukocytosis & Cardiovascular/respiratory multiorgan failure (Retinoic acid-APL Syndrome)

A second generation retinoid

Oral capsules useful for the therapy of severe psoriasis in adults

Synthetic
Lipophilic
Weak acid
A “rexinoid”

PRECISE MOA - UNKNOWN

SELECTIVELY BINDS AND ACTIVATES RETINOID X RECEPTOR SUBTYPES --- ACTIVATED RECEPTORS FUNCTION AS TRANSCRIPTION FACTORS --- REGULATE GENE EXPRESSION THAT CONTROLS CELL DIFFERENTIATION AND PROLIFERATION

Cutaneous manifestations of Cutaneous Tcell Lymphoma (CTCL) in patients refractory to one or more prior systemic therapies

Hyperlipidemia
Hypercholesterolemia
Hypothyroidism

Light-sensitive polyporphyrin oligomer
Purified product of a hematoporphyrin derivative
Red-orange color

Use of a laser light elevates this compound to an excited state which causes radical initiation resulting in ischemic necrosis within a tumor

PhotoDynamic Therapy (PDT) of: Esophageal cancer, Endobronchial non-small cell lung cancer, and Barrett’s Esophagus

Many (CV, CNS, GI, Resp. systems)

Fermentation product of Streptomyces antibioticus

Colorless nucleoside
Weak base
Water soluble

TRANSITION STATE INHIBITOR OF ADENOSINE DEAMINASE which results in INHIBITION OF RIBONUCLEOTIDE REDUCTASE

(antimetabolite)

Adult patient therapy
Alpha-interferon-refractory hairy cell leukemia

Neurologic: Nervousness and insomnia, Depression, Hallucinations

Fermentation product of Escherichia coli & Erwinia carotovoras
Enzyme composed of 4 identical subunits
FW = About 136,000 Da
White
Water-soluble
Active at pH 5-9

INHIBITS GROWTH OF MALIGNANT CELLS THAT ARE ASPARAGINE-DEPENDENT

Results in INHIBITION OF TUMOR PROTEIN SYNTHESIS

Pediatric acute lymphocytic leukemia (ALL)

Decreased Vitamin K-dependent clotting factors --> hemorrhage

Hypersensitivity

Found in various ores, one of which is orpiment
Obtained as a by-product of smelting copper
White solid
Long known in traditional Chinese medicine as Pi Shuang
Two mineral forms exist: Arsenolite (Commonly occurring form–Octahedral or cubic form) & Claudetite (Thermodynamically stable–Monoclinic form)

Precise MOA not fully elucidated
Induces differentiation of APL cells by degrading PML/RAR-α protein
Induces apoptosis
Inhibits angiogenesis

Induction of remission and consolidation in acute promyelocytic leukemia (APL)
- Relapsed from or refractory to retinoid and anthracycline chemotherapy
- Whose APL is characterized by the expression of the t(15;17) translocation or PML/RAR-alpha gene expression

Prolonged QT interval
APL differentiation syndrome: rash, dyspnea, fluid retention, pleural or pericardial effusions
Leukocytosis