Antineplastic+Drugs

Antineoplastic Drugs Lauren and Elle will work together on this page (This is week #15. Deadline is June 6th) Chapter 42 These drugs are used to cure advanced tumors and treatment of many malignancies that cannot be reached by surgery.

**__Principles of Cancer Chemotherapy-__ **

The goal of chemotherapy is to eradicate every viable tumor cell without extensively damaging normal host tissue. Chemotherapy drugs kills or impair susceptible tumor cells by blocking a drug-sensitive biochemical or metabolic pathway. All chemotherapy drugs are extremely cytotoxic with low margins of safety. Need to understand the principles that govern the useful application of cancer chemotherapy.

> > > **__Chemotherapeutic Drugs__ ** **Antineoplastic Alkylating Agents**- Are not cell cycle specific, they are most destructive to rapidly proliferating tissues & seem to cause death only when the cell attempts to divide. <span style="background-color: transparent; color: black; font-family: 'Calibri','sans-serif'; font-size: 15px; text-decoration: none; vertical-align: auto;">**Antimetabolite Agents**- <span style="background-color: transparent; color: black; font-family: 'Calibri','sans-serif'; font-size: 15px; line-height: 115%; text-decoration: none; vertical-align: auto;">Exert their major effects during the S <span style="background-color: transparent; color: black; font-family: 'Calibri','sans-serif'; font-size: 15px; line-height: 115%; text-decoration: none; vertical-align: auto;">(DNA synthesis) Phase of the cell cycle. This interferes with the growth of rapidly proliferating cells throughout the body.
 * 1) <span style="background-color: transparent; color: #000000; display: block; font-family: 'Times New Roman'; font-size: 16px; text-align: left; text-decoration: none;">The tumor must be susceptible to the drug selected, not all tumors are responsive to the same agents.
 * 2) <span style="background-color: transparent; color: #000000; display: block; font-family: 'Times New Roman'; font-size: 16px; text-align: left; text-decoration: none;">The drugs and method of administration must not have an unbearable & systemic toxicity that would prevent the completion of an adaqute course of treatment.
 * 3) <span style="background-color: transparent; color: #000000; display: block; font-family: 'Times New Roman'; font-size: 16px; text-align: left; text-decoration: none;">The dosage & schedule must be calculated to have the maximum contact with the tumor cells & sufficient concentration must be present.
 * 4) <span style="background-color: transparent; color: #000000; display: block; font-family: 'Times New Roman'; font-size: 16px; text-align: left; text-decoration: none;">Drugs more effective when tumor mass is small.
 * 5) <span style="background-color: transparent; color: #000000; display: block; font-family: 'Times New Roman'; font-size: 16px; text-align: left; text-decoration: none;">Anticancer drugs kill cells according to the first order kinetics. Even if 99.99 % of tumor cells are destroyed, the survival of a few or one malignant cell may lead to tumor regrowth, important to give chemotherapy drugs in cycles to maximize tumor cell reduction.
 * 6) <span style="background-color: transparent; color: #000000; display: block; font-family: 'Times New Roman'; font-size: 16px; text-align: left; text-decoration: none;"><span style="background-color: transparent; color: #000000; font-family: Times New Roman; font-size: 16px; text-align: left; text-decoration: none; vertical-align: auto;">Antineoplastic drugs are given in a combination to take advantage of the different mechanisms of action. Combination chemotherapy may prevent or slow the development of resistant strains.
 * 1) <span style="background-color: transparent; color: #000000; display: block; font-family: 'Times New Roman'; font-size: 16px; text-align: left; text-decoration: none;"><span style="background-color: transparent; color: #000000; font-family: 'Calibri','sans-serif'; font-size: 15px; line-height: 115%; text-decoration: none; vertical-align: auto;">Cancer cells may build a resistance to some drugs that previously were effective

<span style="background-color: transparent; color: #000000; display: block; font-family: Calibri,sans-serif; font-size: 15px; text-align: left; text-decoration: none;"><span style="background-color: transparent; color: black; font-family: 'Calibri','sans-serif'; font-size: 15px; text-decoration: none; vertical-align: auto;">**Antibiotics**- <span style="background-color: transparent; color: black; font-family: 'Calibri','sans-serif'; font-size: 15px; line-height: 115%; text-decoration: none; vertical-align: auto;">Numerous antibiotics have been found to exert antineoplastic activity because they have cytotoxic properties. They <span style="background-color: transparent; color: black; font-family: 'Calibri','sans-serif'; font-size: 15px; line-height: 115%; text-decoration: none; vertical-align: auto;">operate by binding with DNA to produce irreversible complexes that inhibit cell division. <span style="background-color: transparent; color: #000000; display: block; font-family: Calibri,sans-serif; font-size: 15px; text-align: left; text-decoration: none;"><span style="background-color: transparent; color: black; font-family: 'Calibri','sans-serif'; font-size: 15px; text-decoration: none; vertical-align: auto;">**Vinca Alkaloids**- <span style="background-color: transparent; color: black; font-family: 'Calibri','sans-serif'; font-size: 15px; line-height: 115%; text-decoration: none; vertical-align: auto;">Stop cell division in metaphase by binding to the microtubular protein tubulin that forms the mitotic spindle. Most <span style="background-color: transparent; color: black; font-family: 'Calibri','sans-serif'; font-size: 15px; line-height: 115%; text-decoration: none; vertical-align: auto;">common toxic effect is leucopenia. <span style="background-color: transparent; color: #000000; display: block; font-family: Calibri,sans-serif; font-size: 15px; text-align: left; text-decoration: none;"><span style="background-color: transparent; color: black; font-family: 'Calibri','sans-serif'; font-size: 15px; text-decoration: none; vertical-align: auto;">**Enzyme**- <span style="background-color: transparent; color: black; font-family: 'Calibri','sans-serif'; font-size: 15px; line-height: 115%; text-decoration: none; vertical-align: auto;">Asparagniase is an enzyme that inhibits protein synthesis in tumor cells by depriving them of the amino acid asparagines. Greatest activity in the G1 phase of the cell cycle. __**Camptothecins**__ __**Taxoids & Epithilones**__
 * From Chinese ornamental tree
 * Mechanism of action
 * inhibits topoisomerase I, which causes single-strand breaks in DNA
 * Examples
 * **Topotecan**- a camptothecin drug
 * Used to Treat
 * metastatic ovarian carcinoma
 * (combined with cytarabine) myelodysplastic syndromes and myelogenous leukemia
 * Side effects
 * myelosuppression (suppresses bone marrow from producing blood cells)
 * diarrhea
 * **Irinotecan**- another camptothecin drug
 * Used to Treat
 * colorectal carcinomas
 * **Paclitaxel**- a taxoid drug
 * From bark of western yew tree
 * Laborious to extract and unable to be synthesized
 * Almost non-water-soluble, so delivered in a formulation that can cause allergic reactions
 * Mechanism of action
 * induces polymerization and stabilization of microtubules
 * Side effects
 * Allergic - managed with steroids, antihistamines or both
 * dyspnea
 * hypotension
 * bronchospasm
 * urticaria
 * erythematous rash
 * Used to Treat
 * metastatic carcinomas of ovaries and breasts
 * **Docetaxel** - similar to Paclitaxel
 * **Ixabepilone**- a epothilone drug
 * From macrolide fermentation of myxobacterium //Sorangium cellulosum//(epothilone A, B) or a synthetic variant (Ixabepilone)
 * Used to Treat
 * metastatic or locally advanced breast cancer
 * Mechanism of action
 * Can displace paxitaxel from binding site
 * Works by stabilizing microtubules
 * Side effects
 * grade III-IV neuropathy (reversible)
 * neutropenia
 * anemia
 * leukopenia
 * thrombocytopenia
 * fatigue
 * myalgia/arthralgia
 * nausea and vomiting
 * alopecia
 * stomatitis/mucositis
 * diarrhea
 * __**Other Agents**__
 * **Hydroxyurea**
 * Mechanism of action
 * inhibits DNA synthesis by blocking the action of ribonucleoside diphosphate reductase
 * absorbed from alimentary tract
 * excreted by urinary system
 * Used to treat
 * chronic myelogenous leukemia
 * reduce peripheral blast counts in acute leukemia
 * sickle cell and other myeloproliferative disorders
 * Side effects
 * myelosuppression
 * megaloblastic anemia
 * **Procarbazine**
 * Originally created as antidepressant
 * Mechanism of action
 * suppresses mitosis
 * produces chromosomal defects
 * absorbed from alimentary tract
 * metabolized by the liver
 * metabolite excreted through urine
 * Used to treat
 * Hodgkins disease
 * lymphomas
 * myelomas
 * Side effects
 * teratogenic (causes birth defects)
 * carcinogenic (causes cancer)
 * monoamine oxidase inhibitor (MAOI)
 * certain drugs and foods can have severe negative interactions with MAOIs
 * alcohol should be avoided
 * **Thalidomide**
 * created as antianxiety/sedative drug
 * Mechanism of action
 * not that well understood
 * antiangiogenesis (starves tumors of blood supply)
 * immune system modulation
 * inhibit tumor necrosis factor-//a// (alpha) production
 * stimulate T-cell production
 * antineoplastic effect is unknown
 * Used to treat
 * multiple myeloma
 * anxiety
 * Hansen's disease (leprosy)
 * AIDS-related cachexia
 * rheumatoid arthritis
 * graft-vs-host disease
 * Side effects
 * teratogenic (causes birth defects)
 * irreversible neurotoxicity
 * sedation
 * rash
 * fatigue
 * constipation
 * increased risk of thromboses
 * **Lenalidomide**
 * Structurally the same as thalidomide
 * Mechanism of action
 * Not well understood
 * For myeloma
 * Induces apoptosis in myeloma cells
 * Inhibits production of cytokines in marrow
 * Stimulates natural killer cell immunity to myeloma cells
 * Decreases binding of myeloma cells to marrow
 * Stimulates the action of dexamethasone
 * For myelodysplastic syndromes
 * Inhibit tumor necrosis factor-a (alpha)
 * Inhibit angiogenesis
 * Stimulates CD4+ and CD8+ cells
 * Used to treat
 * Multiple myeloma (when combined with dexamethasone)
 * Myelodysplastic syndromes
 * Side effects
 * Myelosuppression
 * Fatigure
 * Neuropathies
 * Constipation
 * Somnolence
 * Deep vein thrombosis (combined w/dexamethasone)
 * Birth defects
 * **Arsenic trioxide**
 * Mechanism of action
 * Induce apoptosis by activating cysteine proteases
 * cytodifferentiation
 * Used to treat
 * Promyelocytic leukemia
 * Side effects
 * Lightheadedness
 * Fatigue
 * Musculoskeletal pain
 * Hyperglycemia
 * Peripheral neuropathy
 * Sore throat(When taken orally)
 * Oral blisters (When taken orally)
 * Dry mouth (When taken orally)
 * Retinoic acid syndrome
 * QTc interval prolongation
 * **Decitabine & azacytidine**
 * Mechanism of action
 * Inhibit DNA methylation
 * Results in reactivation of genes that were deactivated by tumor
 * Decitabine
 * Deoxycycline and cytarabine nucleotide derivative
 * (b) Inhibits the process of DNA methyltransferase
 * Azacytidine
 * Nucleotide analogue replaces cytarabine
 * (b) Inhibits DNA methyltransferase
 * Used to treat
 * Myelodysplastic disorders
 * Side effects
 * Myelosuppression
 * Thrombocytopenia
 * Neutropenia
 * Febrile episodes
 * Infections
 * Nausea
 * Vomiting
 * Mucositis
 * Liver dysfunction
 * Creatine elevation
 * **Biphosphonates**
 * Mechanism of action
 * (did not list)
 * Used to treat
 * Manage hypercalcemia and bone pain and skeletal fractures from metastases of
 * Breast carcinomas
 * Prostate carcinomas
 * Lung carcinomas
 * Multiple myeloma
 * Side effects
 * Fevers
 * Flulike syndromes
 * Increases in creatinine
 * Decreases renal function
 * Hypocalcemia
 * Avascular osteonecrosis of the jaw

__**Differentiating Agents: Retinoids**__
 * Subfamilies
 * Retinoid Acid Receptors (RARs)
 * RAR-alpha
 * RAR-beta
 * RAR-gamma
 * Retinoid X Receptors (RXRs)
 * RXR-alpha
 * RXR-beta
 * RXR-gamma
 * Form dimers with each other or other receptors
 * Each subtype controls different target genes
 * Regulates gene transcription
 * Play crucial roles in development and physiologic functioning
 * Inhibit cell growth
 * Inducing differentiation
 * Inducing apoptosis in various tumor cell lines
 * Examples
 * Tretinoin
 * Treats promyelocytic leukemia
 * Induce differentiation and apoptosis
 * Bexarotene
 * Treats cutaneous T-cell lymphoma
 * Activates RXRs
 * Other retinoids
 * Treats oral leukoplakia

__**Biologic Response Modifiers**__
 * Modify host responses
 * Aid in killing cancer cells
 * 3 Main types
 * Interferons
 * Interleukins
 * Colony-stimulating factors
 * Examples
 * Interferons
 * Protein chain of 165 amino acids
 * Antiviral
 * Immunostimulant
 * Anti-proliferative
 * Binds to cell membrane receptors
 * Exact mechanism of action is unknown
 * Treats
 * hairy cell leukemia
 * Kaposi’s sarcoma
 * Chronic hepatitis
 * Chronic myelogenous leukemia
 * Melanoma
 * Other malignancies
 * Aldesleukin (Interleukin)
 * Produced form genetically engineered E. Coli strain
 * Immunoregulatory
 * Enhances lymphocyte mitogenesis
 * Enchnces lymphocyte cytotoxicity
 * Induces killer cells
 * Induces interferon-gamma production
 * Treats
 * Metastatic renal cell carcinoma
 * Metastatic melanoma
 * Side effects
 * Hypotension
 * Weight gain
 * Fluid retention
 * Pulmonary edema
 * Renal dysfunction
 * Fever and chills
 * Pruritis
 * **Oprelvekin (Interleukin)**
 * Stimulates megakaryocytes
 * Reduces marrow toxicity
 * Prevent thrombocytopenia
 * Side effects
 * Fluid retention (and related problems)
 * Headache
 * Myalgia
 * Arthralgia
 * fatigue
 * **Filgrastim and sargramostim (Colony-stimulating)**
 * Not cytotoxic
 * Lessen hematologic toxicity from chemo drugs
 * Allow more chemotherapy to be administered
 * Side effects
 * Flulike symptoms
 * Fever
 * Chills
 * Bone pain
 * Myalgia
 * Pleuritis and pericarditis may be associated
 * **Palifermin**
 * Binds to keratinocyte growth factor receptor
 * Causes epithelial cell proliferation, differentiation, migration
 * Decreases oral mucositis from chemotherapy

__ **Targeted Antineoplastic Therapy** __ - Target specific molecular pathways in tumor cell cycle
 * Tyrosine Kinase Inhibitors
 * Suppresses tumor growth
 * Causes intracellular responses to Tyrosine Kinase overexpression related to certain malignancies
 * Examples
 * Erlotinib – Lung,pancreatic cancer
 * Imatinib – myeloid leukemia, Ph+ leukemia, gastrointestinal stromal
 * Dasatinib – Imatinib resistant cancers
 * Niloinib – Imatinib resistant cancers
 * Lapatinib – Metastatic breast cancer
 * Sorafenib – renal cell carcinoma
 * Sunitinib – renal cell carcinoma, gastrointestinal stromal tumor
 * **Proteasome Inhibitors**
 * Inhibits proteasome, which is essential in regulating the cell cycle, apoptosis, transcription, cell adhesion, angiogenesis, etc.
 * Examples
 * Bortezomib – multiple myeloma, mantle cell lymphoma
 * **Monoclonal Antibodies**
 * Single immunoglobulin antibodies specific to a specific malignancy’s surface antigen
 * Lyses targeted cell
 * Cellular cytotoxicity
 * Apoptosis
 * Examples
 * Rituximab - Lymphomas
 * Trastuzumab – breast cancer
 * Gemtuzumab ozogamicin – acute myelogenous leukemia
 * Ibritumomab and tositumomab - lymphomas
 * Alemtuzumab – chronic lymphocytic leukemia
 * Bevacizumab – colorectal cancer
 * Cetuximab – colorectal cancer, head and neck cancer
 * Panitumumab – colorectal cancer
 * Histone Deacetylase Inhibitors
 * Inhibits important step in regulating gene expression
 * Collapses the DNA around the histones
 * Reduces gene transcription
 * Reactivate apoptosis, differentiation, tumor suppression
 * Examples
 * Vorinosat – treatment-refractory cutaneous T-cell lymphoma
 * Combination Therapy
 * Use agents with different mechanisms of action and different cell-cycle specificity
 * Administer drugs in intermittent courses at max tolerated dosages
 * May combine drugs with radiation
 * May have harmful interactions
 * NSAIDs are of particular note
 * Warfarin
 * Other antineoplastics

__**Implications for Dentistry**__
 * Because of rapid cell division in oral mucosa, the mouth is especially affected by antineoplastic and antitumor drugs
 * Adverse reactions
 * Stomatitis
 * Hemorrhage
 * Acute and chronic infection
 * Rapid progression of caries and perio bone loss
 * Pain may cause improper nutrition