Oncology Exam 1

Source: Plant-derived alkaloid – Catharanthus roseus

(L.) G. Don (Fam.Apocynaceae)

Chemistry– Bisindole alkaloid (minor)• Indole-dihydroindole (indole-indoline)• Yield = 0.001-0.002 % - VERY EXPENSIVE

– Commercial production• Isolate monomeric alkaloids that occur in fargreater amounts from the same plant• Combine the monomers via semi-synthesis• Top portion of VLB = Catharanthine monomer• Bottom portion of VLB = Vindoline monomer

Chemistry– Indole nitrogen does not form salts withacids• Unshared nitrogen electron pair is delocalized– Dihydroindole (indoline) nitrogen atom issufficiently basic to form salts with acids– Close structural relative of vincristine• Differs only in the degree of oxygenation of theN-1 carbon– Colorless• No colored metabolites in body excretions– Marketed as its water soluble sulfate salt

MOA: Inhibit microtubule function; bind to tubulin at interface of heterodimers to promote microtubule dissolution - antimitotics

Common Applications:
-Lymphomas (hodgkin's, non-Hodgkin's)
-breast carcinoma
-testicular carcinoma

Special Adverse Effects:
-Hypotension (most common cardiovascular adverse effect - due to autonomic dysfunction)
-Constipation -- start of therapy includes a bowel regimen of high-fiber diet/med +stool softeners
-Vesicant -- extravasation (skin damage, inflammation, necrosis) [extravasation is treated with heat + local hyaluronidase inj.]

Chemical difference between Vinblastine and Vincristine

Common Applications:
-Lymphomas (Hodgkin's & non-Hodgkin's)
-Acute leukemia
-Many others
- "MOPP" combination

Special Adverse Effects:
-Peripheral/central neuropathies (tingling in the extremities; sever jaw pain; constipation may be severe)
-Vesicant (like VLB)
-Minimal myelosuppression (unlike VLB)

Source: Semi-synthetic from vinblastine

Chemistry:
– Same as vinblastine, except
• “Nor” – without CH2 group at C-8’
– Nor = N ohne radikale
• Notice dehydration across the C-3’/C-4’ bond
– Marketed as its water soluble tartrate salt

Common Applications:
-Non-small cell lung cancer (NSCLC)
-Metastatic breast cancer
-Ovarian/uterine cancer
-Used in relapsed/advanced cases

Special Adverse Effects:
- Shares same as both vinblastine and vincristine (peripheral neuropathies + vesicant)

Source:
– Semi-synthetic
– Fluorinated analog of the semi-syntheticalkaloid vinorelbine

Chemisty:
– Difluoro-substitution on CH2 group of C-4’ethyl chain
– Marketed as water soluble ditartrate salt

Common Applications:
-Phase 2 - Metastatic breast carcinoma in patients whose cancer has recurred or progressed following prior therapy with anthracyclines and taxanes
-Phase 2 - Primary therapy of mesothelioma

Special Adverse Effects:
- Same as other Vinca alkaloids

Source:
-investigational
-semi-synthetic from vinblastine

Chemistry:
– Deacetylvinblastine carboxamide
• Deacetyl- at C-4
• Carboxamide at C-3
– Marketed as its water soluble sulfate salt

Common Applications:
-Metastatic breast cancer
-Lymphomas
-Leukemias
-Lung cancer
-Melanoma

Special Adverse Effects: Shares same as both vinblastine and vincristine (peripheral neuropathies)

–any abnormal swelling in or on a part of the body

–cells multiplying abnormally

non-cancerous, encapsulated and localized tumors

describes a tumor that invades and destroys the tissue in which it originates and can spread to other sites in the body via the bloodstream and lymphatic system

the study and practice of treating malignant tumors

the distant spread of malignant tumor from its site of origin

any cancer that arises in epithelium, the tissue that lines the external and internal organs of the body

cancer that arises in the blood and is immune-system related

a single cell exposed to a carcinogen resulting in genetic changes

certain carcinogens or other factors that a person has been exposed to --- leads to further progression of the growth of the carcinogens

the cell leading to further proliferation and active progression into a tumor, etc.

The immune response to cancer is largely ______ mediated

These types of cells take over:

Exposure to cancer can be influenced by all these different factors:

•Develop from normal genes that regulate normal cellular function called protooncogenes
•Code for proteins such as: growth factors, growth factor receptors, nuclear regulatory proteins, cell-cycle regulators, and signal transducing proteins

Encode proteins that prevent unwanted cellular growth and proliferation of mutant cells

Ex. Growth-inhibitory factors, proteins involved in cell cycle regulation, proteins involved in apoptosis

Gompertz and Cell Population Growth

The process by which as a tumor grows, blood vessels begin to grow and develop on the tumor, which can lead to metastasis

Pha, ses of the Cell Cycle

The part of the cell cycle when cell division occurs

The part of the cell cycle that is known as the dormant phase

The part of the cell cycle where the cell is preparing for DNA synthesis

The part of the cell cycle when DNA synthesis occurs

The part of the cell cycle when the cell is preparing for mitosis and is producing RNA

Transitions through the phases of the cell cycle are controlled by these two things:

5 Different approaches to Cancer Treatment

Intent of Therapy is to eliminate all cancer

Initial treatment to reduce a cancer, which is followed by other treatments

a type of chemotherapy used after curative methods such as surgery

a type of cancer therapy to be used before curative methods such as surgery

Therapy intended to maintain a disease free state

Treatment that is given after cancer has disappeared following the initial therapy

Intent of therapy to minimize growth and/or effets of cancer (control, symptom management, and clinical benefit)

Rituximab MOA

Rituximab Indications:

Rituximab Adverse Effects

Premedications required with Rituximab

Should meds be held prior to treatment with Ritxuimab?

131 I-tositumomab (Bexxar®) MOA:

131 I-tositumomab (Bexxar®) Indications

Premedications used with 131 I-tositumomab (Bexxar®)

131 I-tositumomab (Bexxar®) Drug Interactions:

131 I-tositumomab (Bexxar®) Side Effects:

Ibritumomab Tiuxetan (Zevalin®) MOA:

Ibritumomab Tiuxetan (Zevalin®) Drug Interactions:

Ibritumomab Tiuxetan (Zevalin®) Indications:

Ibritumomab Tiuxetan (Zevalin®) Side Effects:

Alemtuzumab (Campath®) MOA:

Alemtuzumab (Campath®) Indications:

***do not administer as IVP or IV bolus***

Alemtuzumab (Campath®) Toxicities

Alemtuzumab (Campath) Premedications:

Ofatumumab (Arzerra®) MOA:

Ofatumumab (arzerra) indication:

Ofatumumab (Arzerra) Premedications:

Ofatumumab (Arzerra) Side Effects:

Trastuzumab (Herceptin®) MOA:

Trastuzumab (Herceptin®) Indication:

Trastuzumab (Herceptin®) Adverse Effects:

Bevacizumab (Avastin®) Indication:

Bevacizumab (Avastin) Toxicities:

Cetuximab (Erbitux®) Indication:

Cetuximab (Erbitux®) Toxicities:

Panitumumab (Vectibix™) MOA:

Panitumumab (Vectibix™) Indications:

Panitumumab (Vectibix™) Toxicities:

Denosumab (Xgeva™) MOA:

Denosumab (Xgeva™) Indication:

Denosumab (Xgeva™) Adverse Effects:

Ipilimumab (Yervoy™) MOA:

Ipilimumab (Yervoy™) Indication:

Ipilimumab (Yervoy™) Adverse Effects:

Brentuximab (Adcetris™) MOA:

Brentuximab (Adcetris™) Adverse Reactions:

Vinca Alkaloid Resistance occurs by:

Source:
–Plant-derived alkaloid
–Camptotheca acuminata Decne (Fam Nyssaceae)
–Chinese ornamental, introduced into the USA in 1911

Chemistry:
– Pyrrolo[3,4-b]quinoline alkaloid
– Very low water solubility
– The naturally occurring (S)-isomer issignificantly more bioactive than the (R)-isomer
– Intact lactone mandatory for bioactivity butis a liability in aqueous solution becauseof hydrolysis and ring opening
– Physiologic pH favors the ring-openedlactone (carboxylate) which is 1000x lesspotent

MOA: These agents stabilize the cleavablecomplex in which topoisomerase I iscovalently bound to DNA at a singlestrandedbreak site
– The flat camptothecin ring systemintercalates DNA at the site of cleavage,mimicking a DNA base pair
– Lethal DNA damage follows

Source: Semi-synthetic analog of camptothecin(1989)

Chemistry: (S)-9-Dimethylaminomethyl-10-hydroxycamptothecin
– Low water solubility
– Forms nicely water soluble HCl salt at C-9dimethylamino- group

Common applications:
– Ovarian cancer
– Small-cell lung cancer
– Acute myelogenous leukemia (AML)
– Glioma: Via convection-enhanced delivery (slowinfusion of drug directly into tumor andsurrounding brain through implantation of catheter into the interstitial space)

Special Adverse Effects:
– Anemia (40-95%)
– About 50% of patients require erythrocyte(RBC) transfusions

Source:
– Semi-synthetic analog of camptothecin(1985)
– First camptothecin with increased watersolubility
– Japan – 1987
– Therapeutic use: Japan in 1994; USA in Mid- 1990’s

Chemistry:
– Pale yellow
– Low water solubility
– (S)-7-Ethyl-10-hydroxycamptothecin-10-[1,4’]-bipiperidine-1’-carboxylate
• Water soluble HCl salt at the basic piperidine N
– Pro drug of a previously prepared analog
• 7-Ethyl-10-hydroxycamptothecin (1,000x moreactive than irinotecan)

Common Applications
– Colorectal cancer
– Small cell and non-small cell lung cancer
– Glioblastoma: With bevacizumab to extend survival

Special Adverse Effects:
– Like topotecan
– Diarrhea (15-25%) Dose-limiting; can be severe; potentially fatal; Attributed to acetylcholinesterase inhibition: Use loperamide (Imodium® )
– Interstitial pulmonary disease (2010)

Source: A semi-synthetic camptothecin (9-nitrocamptothecin) for oral admin.

Orphan Drug
– Therapy of pancreatic cancer patients whohave failed at least one priorchemotherapy
– HIV- and AIDS-infected pediatric patients

Resistance to this drug is caused by: Decreased expression of topoisomerase I

Mutations in topoisomerase I with decreased binding affinity of drug

Resistance to this drug is the same as Topotecan -- Increased expression of the multidrugresistantgene with elevated P170 glycoprotein levels, leading to
– Enhanced efflux of drug
– Decreased intracellular drug accumulation

Decreased activity or expression ofcarboxylesterase enzyme – decreasedSN-38

Source:
–Plant-derived alkaloid
–Taxus brevifolia Nutt. (Fam. Taxaceae)
–Pacific Yew: A slow-growing evergreen
–May be isolated from other Taxus spp: Taxus baccata – European Yew

Source:
–A new source is the Red Yew that is being grown at Lam Dong Research Center in North Vietnam
–Taxus wallichiana Zucc. (Fam. Taxaceae)
–Growth via “layering technique” : pull leaves down to touch the ground and take root
–Taxol content – 2-4x higher than Wild Yew

Chemistry:
–Colorless diterpene alkaloid
–Low water solubility
–No ionizable functional groups
–Solubilize via 50% Cremophor EL (Polyoxyethylated Castor Oil) and 50% dehydrated alcohol
•Does not alter stability or activity
•Does increase risk of hypersensitivity rxns

Chemistry:
–Many closely related alkaloids have been isolated from various Taxus spp.
–Essential for bioactivity – taxane ring
•“Northern” half–Ensures proper conformation of essential groups–C-13 ester side chain–C-2’ and C-3’ moieties
•“Southern” half–Critical to receptor binding

MOA: promotes assembly of mictrotubules from tubulin dimers and stabilizes microtubules to prevent depolymerization of the tubule into the mitotic spindle

Common Applications:
– Ovarian carcinoma
– Breast carcinoma
– Non-small cell and small cell lungcarcinoma
– Numerous others
– Drug combinations: Paclitaxel can upregulate thymidinephosphorylase, one activating enzyme of Capecitabine (Xeloda®)

Special Adverse Effects:
– Hypersensitivity reactions (20-40%)
– Sensory: Peripheral neuropathies
– Cardiac conduction disturbances: Transient sinus bradycardia

Source: a diterpene alkaloid extracted from the needles of the European Yew (Taxus baccata L.)

Chemistry: Semi-synthetic via esterification of the C-13 alcohol of 10-deacetylbaccatin III
– White (colorless) compound
– Low water solubility
– Greater water solubility than paclitaxelbecause of presence of C-10 alcoholinstead of C-10 acetyl ester (paclitaxel)
– Dissolved in aqueous ethanolic (13%EtOH) Polysorbate 80

Special Adverse Effects:
– Same as paclitaxel (taxol)
– Sensory: Peripheral neuropathies
– Fluid retention (may be significant)

Source– A semi-synthetic taxoid prepared from 10-deacetylbaccatin III

Potential Applications:
– Selected for development because of preclinical evidence of activity against multidrug resistant tumors
– Poor substrate for the P-glycoprotein drugefflux pump'
– Phase I and Phase II studies: breastcancer in taxane-resistant patients
– Phase III studies: advanced pancreatic cancer and advanced bladder cancer

Potential Applications:
–FDA approves for use in second-line therapy for metastaticprostatic cancer (increased survival by30%) when combined with prednisone/prednisolone in patients who have already been treated with docetaxel
– Second line option that complements existing therapies

Special Adverse Effect: Same as paclitaxel (taxol)
– Most common adverse effects leading totermination of therapy were Neutropenia & Renal failure

Resistance to this class of drugs occurs by: Increased expression of the multidrug-resistant gene with elevated P170 glycoprotein levels
–Enhanced efflux of drug
–Decreased intracellular drug accumulation