Antineoplastic Agents Flashcards
Antimetabolites
= *Structural Analogs of Nucleosides of their Precursors
(Except Hydroxyurea)
- Function Either By:
(1) Inhibiting Enzymes that MAKE Nucleosides
(2) Incorporation INTO Nucleic Acids
(Inhibition of DNA and RNA Synthesis;
Disruption of RNA Synthesis/ Processing/ Function)
*Cell-Cycle Specific:
=> *Primarily Function @ G1 and/or S Phase of Cell Cycle
(G1 = preparing building blocks for DNA synthesis)
Resistance:
*Are NOT Substrates for the MDR Mechanism generally
Major Classes:
1) Folate Analogs:
_*Methotrexate (MTX)
2) Pyrimidine Analogs:
_5-Fluorouracil
_Cytosine Arabinoside
3) Purine Analogs:
_6-Mercaptopurine
_6Thioguanine
4) “Other”: *Hydroxyurea
_Inhibits Ribonucleotide Reductase
_Generally only used in Combination or as a Radiation Sensitizer.
*Methotrexate (MTX)
Folate Antimetabolites
1) *Mechanism of Action:
= *Inhibits Dihydrofolate Reductase
2) *Inhibiting Purine, Pyrimidine, and Amino Acid Synthesis
3) *Polyglutamylated form is the *More Active Metabolite.
4) *Selectivity:
=> Formation and *Retention of Polyglutamate Derivatives in Tumor Cells
5) Uses:
(i) *Acute Leukemias (extremely effective)
(ii) *Choriocarcinomas
(Both of these are very rapidly dividing cancer, hence why the drug is very effective.)
6) Toxicity:
(i) *Myelosuppression
=> *Can be Reduced with *Leucovorin (Folinic Acid) “Rescue”
*5-Fluorouracil (5-FU)
Pyrimidine Antimetabolite
Mechanism:
(1) *Inhibits Thymidylate Synthetase (TS)
(when converted to 5-FdUMP)
(2) *Incorporates into DNA and RNA
(when converted to FdUTP and FUTP)
*Leucovorin Enhances Activity by promoting binding.
Uses:
(1) *Solid Tumors: *GI, *Mainly *Colon; Breast
(2) *Topical: *Skin Warts and *Skin Lesions
Cytosine Arabinoside (Ara-C)
Pyrimidine Antimetabolite
Mechanism:
1) *Incorporates into DNA via *Competition with *dCTP
(Deoxycytidine)
2) *Inhibits DNA Synthesis
Use: *Potent Anti-Leukemic
(e.g. AML: Acute Myeloblastic Leukemia)
6-Mercaptopurine
Purine Antimetabolite
Mechanism: *Inhibits DNA and Purine Synthesis
Uses:
1) Leukemias
2) Lymphomas
Toxicity:
1) *Pancreatitis
2) *Hepatic Dysfunction
6-Thioguanine
Purine Antimetabolite
Mechanism: *Inhibits DNA and Purine Synthesis
Uses:
1) Leukemias
2) Lymphomas
Toxicity:
1) *Pancreatitis
2) *Hepatic Dysfunction
Hydroxyurea
Analog of Urea
Mechanism:
1) *Inhibits Ribonucleotide Reductase
(enzyme for conversion of ribonucleotides to deoxyribonucleotides)
2) *Inhibits DNA Synthesis
Uses:
1) Radiation Sensitization
2) Leukemias
Cyclophosphamide
Alkylating Agents:
_Not Cell-cycle Specific
_Not Substrates for MDR Pump
1) Mustards: Nitrogen Mustards:
(i) **Cyclophosphamide
(ii) *Melphalan
(iii) *Chlorambucil
2) Nitrosureas:
(i) *Carmustine (BCNU)
(ii) *Lomustine (CCNU)
(iii) Streptozotocin
3) Triazenes: *Temozolomide
________________________
Nitrogen and Sulfur Mustards:
=> Related to Mustard Gas.
**Nitrogen Mustards contain a *BischloroethylAMINE Group
(Sulfur mustards contain a bischloroethylsulfide group)
Mustards: Nitrogen Mustards:
(i) **Cyclophosphamide
(ii) *Melphalan
(iii) *Chlorambucil
Mechanism:
1) *Alkylates DNA (Cross-links DNA)
2) Inhibits DNA Synthesis
Resistance:
1) *Increased GSH/GSH Metabolic Enzymes
(GSH = Glutathione)
2) Increased Alkyltransferase Repair
Uses: 1) *CNS Tumors (*Nitrosureas) 2) Varies by Drug (lymphomas, leukemias, solid: breast, lung, ovarian)
Toxicity: 1) *Myelosuppression 2) *Secondary Neoplasias 3) *Hemorrhagic Cystitis (cyclophosphamide metabolite; contains tear gas)
________________________
Nitrosureas
**Cross the BBB: **Used for Primary Brain Tumors!!
Nitrosureas:
1) *Carmustine (BCNU)
2) *Lomustine (CCNU)
3) Streptozotocin:
_Sugar group confers High Affinity for Pancreas.
=> *Tumors @ Islets of Langerhans (Pancreas)
________________________
Triazenes: *Temozolomide
Crosses BBB.
Uses:
_Gliomas
Carmustine (BCNU)
Alkylating Agents:
_Not Cell-cycle Specific
_Not Substrates for MDR Pump
1) Mustards: Nitrogen Mustards:
(i) **Cyclophosphamide
(ii) *Melphalan
(iii) *Chlorambucil
2) Nitrosureas:
(i) *Carmustine (BCNU)
(ii) *Lomustine (CCNU)
(iii) Streptozotocin
3) Triazenes: *Temozolomide
________________________
Nitrogen and Sulfur Mustards:
=> Related to Mustard Gas.
**Nitrogen Mustards contain a *BischloroethylAMINE Group
(Sulfur mustards contain a bischloroethylsulfide group)
Mustards: Nitrogen Mustards:
(i) **Cyclophosphamide
(ii) *Melphalan
(iii) *Chlorambucil
Mechanism:
1) *Alkylates DNA (Cross-links DNA)
2) Inhibits DNA Synthesis
Resistance:
1) *Increased GSH/GSH Metabolic Enzymes
(GSH = Glutathione)
2) Increased Alkyltransferase Repair
Uses: 1) *CNS Tumors (*Nitrosureas) 2) Varies by Drug (lymphomas, leukemias, solid: breast, lung, ovarian)
Toxicity: 1) *Myelosuppression 2) *Secondary Neoplasias 3) *Hemorrhagic Cystitis (cyclophosphamide metabolite; contains tear gas)
________________________
Nitrosureas
**Cross the BBB: **Used for Primary Brain Tumors!!
Nitrosureas:
1) *Carmustine (BCNU)
2) *Lomustine (CCNU)
3) Streptozotocin:
_Sugar group confers High Affinity for Pancreas.
=> *Tumors @ Islets of Langerhans (Pancreas)
________________________
Triazenes: *Temozolomide
Crosses BBB.
Uses:
_Gliomas
Lomustine (CCNU)
Alkylating Agents:
_Not Cell-cycle Specific
_Not Substrates for MDR Pump
1) Mustards: Nitrogen Mustards:
(i) **Cyclophosphamide
(ii) *Melphalan
(iii) *Chlorambucil
2) Nitrosureas:
(i) *Carmustine (BCNU)
(ii) *Lomustine (CCNU)
(iii) Streptozotocin
3) Triazenes: *Temozolomide
________________________
Nitrogen and Sulfur Mustards:
=> Related to Mustard Gas.
**Nitrogen Mustards contain a *BischloroethylAMINE Group
(Sulfur mustards contain a bischloroethylsulfide group)
Mustards: Nitrogen Mustards:
(i) **Cyclophosphamide
(ii) *Melphalan
(iii) *Chlorambucil
Mechanism:
1) *Alkylates DNA (Cross-links DNA)
2) Inhibits DNA Synthesis
Resistance:
1) *Increased GSH/GSH Metabolic Enzymes
(GSH = Glutathione)
2) Increased Alkyltransferase Repair
Uses: 1) *CNS Tumors (*Nitrosureas) 2) Varies by Drug (lymphomas, leukemias, solid: breast, lung, ovarian)
Toxicity: 1) *Myelosuppression 2) *Secondary Neoplasias 3) *Hemorrhagic Cystitis (cyclophosphamide metabolite; contains tear gas)
________________________
Nitrosureas
**Cross the BBB: **Used for Primary Brain Tumors!!
Nitrosureas:
1) *Carmustine (BCNU)
2) *Lomustine (CCNU)
3) Streptozotocin:
_Sugar group confers High Affinity for Pancreas.
=> *Tumors @ Islets of Langerhans (Pancreas)
________________________
Triazenes: *Temozolomide
Crosses BBB.
Uses:
_Gliomas
Temozolomide
Alkylating Agents:
_Not Cell-cycle Specific
_Not Substrates for MDR Pump
1) Mustards: Nitrogen Mustards:
(i) **Cyclophosphamide
(ii) *Melphalan
(iii) *Chlorambucil
2) Nitrosureas:
(i) *Carmustine (BCNU)
(ii) *Lomustine (CCNU)
(iii) Streptozotocin
3) Triazenes: *Temozolomide
________________________
Nitrogen and Sulfur Mustards:
=> Related to Mustard Gas.
**Nitrogen Mustards contain a *BischloroethylAMINE Group
(Sulfur mustards contain a bischloroethylsulfide group)
Mustards: Nitrogen Mustards:
(i) **Cyclophosphamide
(ii) *Melphalan
(iii) *Chlorambucil
Mechanism:
1) *Alkylates DNA (Cross-links DNA)
2) Inhibits DNA Synthesis
Resistance:
1) *Increased GSH/GSH Metabolic Enzymes
(GSH = Glutathione)
2) Increased Alkyltransferase Repair
Uses: 1) *CNS Tumors (*Nitrosureas) 2) Varies by Drug (lymphomas, leukemias, solid: breast, lung, ovarian)
Toxicity: 1) *Myelosuppression 2) *Secondary Neoplasias 3) *Hemorrhagic Cystitis (cyclophosphamide metabolite; contains tear gas)
________________________
Nitrosureas
**Cross the BBB: **Used for Primary Brain Tumors!!
Nitrosureas:
1) *Carmustine (BCNU)
2) *Lomustine (CCNU)
3) Streptozotocin:
_Sugar group confers High Affinity for Pancreas.
=> *Tumors @ Islets of Langerhans (Pancreas)
________________________
Triazenes: *Temozolomide
Crosses BBB.
Uses:
_Gliomas
Streptozotocin
Alkylating Agents:
_Not Cell-cycle Specific
_Not Substrates for MDR Pump
1) Mustards: Nitrogen Mustards:
(i) **Cyclophosphamide
(ii) *Melphalan
(iii) *Chlorambucil
2) Nitrosureas:
(i) *Carmustine (BCNU)
(ii) *Lomustine (CCNU)
(iii) Streptozotocin
3) Triazenes: *Temozolomide
________________________
Nitrogen and Sulfur Mustards:
=> Related to Mustard Gas.
**Nitrogen Mustards contain a *BischloroethylAMINE Group
(Sulfur mustards contain a bischloroethylsulfide group)
Mustards: Nitrogen Mustards:
(i) **Cyclophosphamide
(ii) *Melphalan
(iii) *Chlorambucil
Mechanism:
1) *Alkylates DNA (Cross-links DNA)
2) Inhibits DNA Synthesis
Resistance:
1) *Increased GSH/GSH Metabolic Enzymes
(GSH = Glutathione)
2) Increased Alkyltransferase Repair
Uses: 1) *CNS Tumors (*Nitrosureas) 2) Varies by Drug (lymphomas, leukemias, solid: breast, lung, ovarian)
Toxicity: 1) *Myelosuppression 2) *Secondary Neoplasias 3) *Hemorrhagic Cystitis (cyclophosphamide metabolite; contains tear gas)
________________________
Nitrosureas
**Cross the BBB: **Used for Primary Brain Tumors!!
Nitrosureas:
1) *Carmustine (BCNU)
2) *Lomustine (CCNU)
3) Streptozotocin:
_Sugar group confers High Affinity for Pancreas.
=> *Tumors @ Islets of Langerhans (Pancreas)
________________________
Triazenes: *Temozolomide
Crosses BBB.
Uses:
_Gliomas
Cisplatin
Platinum Compounds
Alkylating-Like Agents
1) **Cisplatin
2) *Oxaliplatin
- Not Cell-cycle Specific
- Not Substrates MDR Pump
Mechanism:
1) *Form Intra-strand and Inter-strand DNA Cross-Links
=> Results in DNA Breaks
2) *Inhibits DNA Synthesis
(Only Cis form is active; trans platinum is inactive.)
(Activated when in contact with water.
(Was accidentally discovered to block bacterial cell division.)
Resistance:
1) *Increased GSH/GSH-Metabolic Enzymes
2) *Increased DNA Repair
Uses: *Solid Tumors:
1) *Testicular Cancers
Toxicity:
1) *Nephrotoxicity
2) *Ototoxicity
Oxaliplatin
Platinum Compounds
Alkylating-Like Agents
1) **Cisplatin
2) *Oxaliplatin
- Not Cell-cycle Specific
- Not Substrates MDR Pump
Mechanism:
1) *Form Intra-strand and Inter-strand DNA Cross-Links
=> Results in DNA Breaks
2) *Inhibits DNA Synthesis
(Only Cis form is active; trans platinum is inactive.)
(Activated when in contact with water.
(Was accidentally discovered to block bacterial cell division.)
Resistance:
1) *Increased GSH/GSH-Metabolic Enzymes
2) *Increased DNA Repair
Uses: *Solid Tumors:
1) *Testicular Cancers
Toxicity:
1) *Nephrotoxicity
2) *Ototoxicity
Mitoxantrone
DNA-Interacting Antibiotics
(Multi-ring Anthracyclines)
*Not Cell-cycle Specific.
_But G phases (Growth) is More Susceptible.
Rubicins:
(i) *Doxorubicin
(ii) *Daunorubicin
Mechanism:
1) *Intercalate into DNA
(Disrupts DNA and RNA synthesis)
2) *Topoisomerase II Inhibition
(Due to distortion of double-helix: DNA strand breaks and DNA-protein cross-links)
3) *Generate ROS
Resistance:
=> *Are Substrates for MDR Pump!
(Due to planar structure)
Toxicity: (Ruby Red Cardiotox!) *Cardiotoxicity: 1) *Acute: Arrhythmias 2) *Chronic: CHF (b/c Heart is a major producer of ROS anyway)
____________________
*Mitoxantrone:
_Similar Structure and Mechanism to Anthracyclines
_However, *Reduced Cardiotoxicity!!
=> Due to *Reduced ROS Formation
Doxorubicin
DNA-Interacting Antibiotics
(Multi-ring Anthracyclines)
*Not Cell-cycle Specific.
_But G phases (Growth) is More Susceptible.
Rubicins:
(i) *Doxorubicin
(ii) *Daunorubicin
Mechanism:
1) *Intercalate into DNA
(Disrupts DNA and RNA synthesis)
2) *Topoisomerase II Inhibition
(Due to distortion of double-helix: DNA strand breaks and DNA-protein cross-links)
3) *Generate ROS
Resistance:
=> *Are Substrates for MDR Pump!
(Due to planar structure)
Toxicity: (Ruby Red Cardiotox!) *Cardiotoxicity: 1) *Acute: Arrhythmias 2) *Chronic: CHF (b/c Heart is a major producer of ROS anyway)
____________________
*Mitoxantrone:
_Similar Structure and Mechanism to Anthracyclines
_However, *Reduced Cardiotoxicity!!
=> Due to *Reduced ROS Formation
Daunorubicin
DNA-Interacting Antibiotics
(Multi-ring Anthracyclines)
*Not Cell-cycle Specific.
_But G phases (Growth) is More Susceptible.
Rubicins:
(i) *Doxorubicin
(ii) *Daunorubicin
Mechanism:
1) *Intercalate into DNA
(Disrupts DNA and RNA synthesis)
2) *Topoisomerase II Inhibition
(Due to distortion of double-helix: DNA strand breaks and DNA-protein cross-links)
3) *Generate ROS
Resistance:
=> *Are Substrates for MDR Pump!
(Due to planar structure)
Toxicity: (Ruby Red Cardiotox!) *Cardiotoxicity: 1) *Acute: Arrhythmias 2) *Chronic: CHF (b/c Heart is a major producer of ROS anyway)
____________________
*Mitoxantrone:
_Similar Structure and Mechanism to Anthracyclines
_However, *Reduced Cardiotoxicity!!
=> Due to *Reduced ROS Formation
Plant (Natural) Products
Microtubule Inhibitors:
(“Spindle Poisons”)
1) Stabilizers: Taxanes:
_Paclitaxel (Taxol)
2) Destabilizers: Vinca Alkaloids:
_Vincristine (Oncovin)
_*Vinblastine (Velban)
Microtubule Inhibitors
(“Spindle Poisons”)
_Active During Mitosis, where they perturb the Mitotic Spindle and Disrupt Proper Chromosome Segregation
____________________
Topoisomerase Inhibitors:
1) Topoisomerase II Inhibitors:
_*Epipodophyllotoxins:
(i) *Etoposide *(VM-16)
(ii) *Teniposide *(VM-26)
2) Topoisomerase I Inhibitors:
_*Camptothecins: *Irinotecan
- Topoisomerases Unwind Tangled DNA by cutting one strand so another can pass through the break:
(1) Topo I: Relaxes Supercoils Ahead of DNA replication fork.
(2) Topo II: Allows Daughter strands to pass THROUGH one another. - Topoisomerase Inhibitors Stabilize the DNA-Topo Intermediate in the Cut state, Leading to DNA Breaks.
Paclitaxel
Taxanes
Source: Yew Tree Bark
(FSU total synthesis: Taxol)
Microtubule Inhibitors
(“Spindle Poisons”)
*Paclitaxel (Taxol)
Mechanism:
*Stabilizes Microtubule;
= *Prevents Tubulin Depolymerization
= *Inhibits Microtubule Disassembly
Uses: *Solid Tumors
(ovarian, breast, lung)
Resistance:
*Substrate for MDR Pump
Toxicity:
1) *Peripheral Neuropathy
2) Cumulative Myelosuppression
Vinblastine
Vinca Alkaloids
(Looks Like Pacman eating Ghost)
(Complex Plant Derivatives)
Microtubule Inhibitors
(“Spindle Poisons”)
- Specificity: *M Phase (Mitosis).
- Vinblastine, *Vincristine
Mechanism:
1) *Destabilizes Microtubules
2) *Mitotic Arrest
Resistance: *MDR Efflux Pumps
Toxicity:
1) Neurotoxicity (Vincristine)
(*Muscle Weakness, *Peripheral Neuropathy)
Vincristine
Vinca Alkaloids
(Looks Like Pacman eating Ghost)
(Complex Plant Derivatives)
Microtubule Inhibitors
(“Spindle Poisons”)
- Specificity: *M Phase (Mitosis).
- Vinblastine, *Vincristine
Mechanism:
1) *Destabilizes Microtubules
2) *Mitotic Arrest
Resistance: *MDR Efflux Pumps
Toxicity:
1) Neurotoxicity (Vincristine)
(*Muscle Weakness, *Peripheral Neuropathy)
Etoposide
Epipodophyllotoxins
(Derived from Mayapple / American Mandrake)
Topoisomerase II Inhibitor
1) *Etoposide *(VP-16)
2) *Teniposide *(VM-26
Mechanism:
1) *Stabilizes Topo II-DNA Intermediate,
2) *Leading to DNA Breaks
(Mechanism and structure similar to Anthracyclines; S and G2 phases most sensitive)
Resistance:
1) *MDR Pump
2) *Decreased or *Mutant Topo II
3) *p53 Mutation
(p53 mediates response to DNA damage)
Toxicity:
1) *Leukopenia *(Dose-Limiting)
2) *Hepatotoxicity *(High-Dose)
____________________
- Topoisomerases Unwind Tangled DNA by cutting one strand so another can pass through the break:
(1) Topo I: Relaxes Supercoils Ahead of DNA replication fork.
(2) Topo II: Allows Daughter strands to pass THROUGH one another. - Topoisomerase Inhibitors Stabilize the DNA-Topo Intermediate in the Cut state, Leading to DNA Breaks.
Teniposide
Epipodophyllotoxins
(Derived from Mayapple / American Mandrake)
Topoisomerase II Inhibitor
1) *Etoposide *(VP-16)
2) *Teniposide *(VM-26
Mechanism:
1) *Stabilizes Topo II-DNA Intermediate,
2) *Leading to DNA Breaks
(Mechanism and structure similar to Anthracyclines; S and G2 phases most sensitive)
Resistance:
1) *MDR Pump
2) *Decreased or *Mutant Topo II
3) *p53 Mutation
(p53 mediates response to DNA damage)
Toxicity:
1) *Leukopenia *(Dose-Limiting)
2) *Hepatotoxicity *(High-Dose)
____________________
- Topoisomerases Unwind Tangled DNA by cutting one strand so another can pass through the break:
(1) Topo I: Relaxes Supercoils Ahead of DNA replication fork.
(2) Topo II: Allows Daughter strands to pass THROUGH one another. - Topoisomerase Inhibitors Stabilize the DNA-Topo Intermediate in the Cut state, Leading to DNA Breaks.
Irinotecan
Camptothecins
(Derived from Happy Tree)
Topoisomerase I Inhibitor
*Irinotecan
Mechanism:
1) *Stabilizes Topo I-DNA Intermediate
Resistance:
1) Reduced levels or Altered Affinity of Topo I (Mutant)
2) Weak Substrate for MDR Pump
Uses: *Solid Tumors
(ovarian, colon, small cell lung cancers: SCLC)
____________________
- Topoisomerases Unwind Tangled DNA by cutting one strand so another can pass through the break:
(1) Topo I: Relaxes Supercoils Ahead of DNA replication fork.
(2) Topo II: Allows Daughter strands to pass THROUGH one another. - Topoisomerase Inhibitors Stabilize the DNA-Topo Intermediate in the Cut state, Leading to DNA Breaks.
Hormone-Targeted Chemotherapy
Goal: *Turn OFF Hormone Signaling
Uses:
1) *Endometrial
2) *Breast
3) *Prostate
4) (Sometimes Lung Cancer b/c Estrogen Receptor is expressed in Lung)
Approaches:
1) *Compete with Endogenous Hormone for Receptor Binding
2) *Block Production of Endogenous Hormone
**Toxicities are Much Milder than Other Chemotherapeutics
_B/c Not actually Killing the cells
Flutamide
Anti-Androgenic Agents
1) Anti-Androgens: *Flutamide
Mechanism:
*Competitive Antagonist of Androgens
Use: *Prostate Cancer
2) LHRH Agonists: *Leuprolide
Mechanism:
*Inhibits Androgen Release via Downregulation
(with chronic administration)
Use: *Prostate Cancer
(and GnRH antagonist)
Leuprolide
Anti-Androgenic Agents
1) Anti-Androgens: *Flutamide
Mechanism:
*Competitive Antagonist of Androgens
Use: *Prostate Cancer
2) LHRH Agonists: *Leuprolide
Mechanism:
*Inhibits Androgen Release via Downregulation
(with chronic administration)
Use: *Prostate Cancer
(and GnRH antagonist)
Tamoxifen
Anti-Estrogenic Agents
1) Anti-Estrogens: *Tamoxifen
Mechanism:
*Competitive Antagonist of Estrogen
Use:
_Prevents or Slows Growth of Estrogen-Dependent Tumors:
*Breast Cancer
2) Aromatase Inhibitors: *Anastrazole
Mechanism:
1) *Inhibits Aromatase,
2) *Blocking Estrogen Synthesis
Use:
_Breast Cancer in Post-Menopausal Women
Anastrazole
Anti-Estrogenic Agents
1) Anti-Estrogens: *Tamoxifen
Mechanism:
*Competitive Antagonist of Estrogen
Use:
_Prevents or Slows Growth of Estrogen-Dependent Tumors:
*Breast Cancer
2) Aromatase Inhibitors: *Anastrazole
Mechanism:
1) *Inhibits Aromatase,
2) *Blocking Estrogen Synthesis
Use:
_Breast Cancer in Post-Menopausal Women
Corticosteroids
Glucocorticoids
Mechanism:
_*Lyse Malignant T lymphocytes
Use:
1) *Lymphomas
2) *Acute Lymphocytic Leukemia
Bleomycin
Miscellaneous Agent
Mechanism:
*Breaks DNA via *Free Radicals
Toxicity:
_*Minimal Marrow Toxicity
Aspariginase
Miscellaneous Agent
Mechanism:
_*Inhibits Protein Synthesis
Resistance:
_*Increase Asparagine Synthetase Activity in Tumor cell
Use: *Childhood Acute Leukemia
Toxicity: *Hypersensitivity Reactions
Targeted Therapies of Cancer:
“New Wave”
**Target Specific Molecular Pathways or Mediators of the Malignant Phenotype.
Efficacy:
_More Effective than conventional therapies,
_But only in cases where target is a prominent factor in the disease
Toxicities:
_Less than conventional therapies
_Infusion Reactions are common for most IV agents.
1) Tyrosine Kinase Inhibitors
(-Tinibs)
2) Disruptors of Gene Expression, Protein Translation, Proteolysis
3) Monoclonal Antibodies (-Mabs)
4) Cytokines and Immunomodulators
5) Differentiating Agents
6) Other
Imatinib
Tyrosine Kinase Inhibitors
= Analogs of ATP
Designed Against Kinases that Activate Pro-Growth, Pro-Survival Pathways.
Use is guided by known frequent Deregulation of a Receptor-Pathway in a given cancer.
Mechanisms:
1) *Promote Apoptosis
2) *Inhibit Growth Factors
3) *Inhibit Angiogenesis
4) *Inhibit Proliferation
Usually Given *p.o. (orally)
Adverse Effects:
1) *Skin and *Mucosal Effects
2) *Fatigue
___________________
1) *Imatinib:
Mechanism: *Inhibits Abl Kinase
*(ABL-BCR Fusion Gene)
(Philadelphia Chromosome)
Use: *Drug of Choice!:
*Chronic Myelogenous Leukemia
___________________
2) Gefetinib:
Mechanism: *Inhibits EGFR
(Epidermal Growth Factor Receptor)
Use: *Oral Treatment of NSCLC
(Non-small cell lung cancer)
(Most effective in Never-Smoker Females and Asians)
___________________
3) Lapatinib:
Mechanism: *Inhibits HER-2
Use:
*Advanced/Metastatic Breast Cancer
___________________
4) Sunitinib (not bold this yr)
Mechanism: Blocks VEGFR
(Vascular Endothelial Growth Factor Receptor)
Use: Renal Cancer
Not as selective for desired kinases
(good or bad?)
Gefetinib
Tyrosine Kinase Inhibitors
= Analogs of ATP
Designed Against Kinases that Activate Pro-Growth, Pro-Survival Pathways.
Use is guided by known frequent Deregulation of a Receptor-Pathway in a given cancer.
Mechanisms:
1) *Promote Apoptosis
2) *Inhibit Growth Factors
3) *Inhibit Angiogenesis
4) *Inhibit Proliferation
Usually Given *p.o. (orally)
Adverse Effects:
1) *Skin and *Mucosal Effects
2) *Fatigue
___________________
1) *Imatinib:
Mechanism: *Inhibits Abl Kinase
*(ABL-BCR Fusion Gene)
(Philadelphia Chromosome)
Use: *Drug of Choice!:
*Chronic Myelogenous Leukemia
___________________
2) Gefetinib:
Mechanism: *Inhibits EGFR
(Epidermal Growth Factor Receptor)
Use: *Oral Treatment of NSCLC
(Non-small cell lung cancer)
(Most effective in Never-Smoker Females and Asians)
___________________
3) Lapatinib:
Mechanism: *Inhibits HER-2
Use:
*Advanced/Metastatic Breast Cancer
___________________
4) Sunitinib (not bold this yr)
Mechanism: Blocks VEGFR
(Vascular Endothelial Growth Factor Receptor)
Use: Renal Cancer
Not as selective for desired kinases
(good or bad?)
Lapatinib
Tyrosine Kinase Inhibitors
= Analogs of ATP
Designed Against Kinases that Activate Pro-Growth, Pro-Survival Pathways.
Use is guided by known frequent Deregulation of a Receptor-Pathway in a given cancer.
Mechanisms:
1) *Promote Apoptosis
2) *Inhibit Growth Factors
3) *Inhibit Angiogenesis
4) *Inhibit Proliferation
Usually Given *p.o. (orally)
Adverse Effects:
1) *Skin and *Mucosal Effects
2) *Fatigue
___________________
1) *Imatinib:
Mechanism: *Inhibits Abl Kinase
*(ABL-BCR Fusion Gene)
(Philadelphia Chromosome)
Use: *Drug of Choice!:
*Chronic Myelogenous Leukemia
___________________
2) Gefetinib:
Mechanism: *Inhibits EGFR
(Epidermal Growth Factor Receptor)
Use: *Oral Treatment of NSCLC
(Non-small cell lung cancer)
(Most effective in Never-Smoker Females and Asians)
___________________
3) Lapatinib:
Mechanism: *Inhibits HER-2
Use:
*Advanced/Metastatic Breast Cancer
___________________
4) Sunitinib (not bold this yr)
Mechanism: Blocks VEGFR
(Vascular Endothelial Growth Factor Receptor)
Use: Renal Cancer
Not as selective for desired kinases
(good or bad?)
Sunitinib
Tyrosine Kinase Inhibitors
= Analogs of ATP
Designed Against Kinases that Activate Pro-Growth, Pro-Survival Pathways.
Use is guided by known frequent Deregulation of a Receptor-Pathway in a given cancer.
Mechanisms:
1) *Promote Apoptosis
2) *Inhibit Growth Factors
3) *Inhibit Angiogenesis
4) *Inhibit Proliferation
Usually Given *p.o. (orally)
Adverse Effects:
1) *Skin and *Mucosal Effects
2) *Fatigue
___________________
1) *Imatinib:
Mechanism: *Inhibits Abl Kinase
*(ABL-BCR Fusion Gene)
(Philadelphia Chromosome)
Use: *Drug of Choice!:
*Chronic Myelogenous Leukemia
___________________
2) Gefetinib:
Mechanism: *Inhibits EGFR
(Epidermal Growth Factor Receptor)
Use: *Oral Treatment of NSCLC
(Non-small cell lung cancer)
(Most effective in Never-Smoker Females and Asians)
___________________
3) Lapatinib:
Mechanism: *Inhibits HER-2
Use:
*Advanced/Metastatic Breast Cancer
___________________
4) Sunitinib (not bold this yr)
Mechanism: Blocks VEGFR
(Vascular Endothelial Growth Factor Receptor)
Use: Renal Cancer
Not as selective for desired kinases
(good or bad?)
HDAC Inhibitors
Transcription, Translation, and Proteolysis Disruptors
HDAC Inhibitors:
_*Prevent Histone Deacetylation
Rapamycins (Sirolimus):
1) *Block New Protein Synthesis
2) *Stimulate Autophagy
Proteasome Inhibitors:
_Bortezomib
_*Block Protein Turnover by the Proteasome; Induce Apoptosis
Use: *Multiple Myeloma (1st line)
Sirolimus
Transcription, Translation, and Proteolysis Disruptors
HDAC Inhibitors:
_*Prevent Histone Deacetylation
Rapamycins (Sirolimus):
1) *Block New Protein Synthesis
2) *Stimulate Autophagy
Proteasome Inhibitors:
_Bortezomib
_*Block Protein Turnover by the Proteasome; Induce Apoptosis
Use: *Multiple Myeloma (1st line)
Bortezomib
Transcription, Translation, and Proteolysis Disruptors
HDAC Inhibitors:
_*Prevent Histone Deacetylation
Rapamycins (Sirolimus):
1) *Block New Protein Synthesis
2) *Stimulate Autophagy
Proteasome Inhibitors:
_Bortezomib
_*Block Protein Turnover by the Proteasome; Induce Apoptosis
Use: *Multiple Myeloma (1st line)
Rituximab
Monoclonal Antibodies
*All Must be Given by Infusion
Can Cause Infusion Reactions:
_Rash, *Edema, *Hypotension, Bronchospasms;
_Rarely, Anaphylaxis
1) *Rituximab:
_Antigen: *CD20
_Use: *B cell Lymphoma
_Mechanism: ADCC
2) *Alemtuzumab:
Antigen: *CD52
Use: *T cell Lymphoma
Mechanism: ADCC
3) *Trastuzumab:
Antigen: *HER-2/Neu Tyrosine Kinase
Use: *Breast Cancer
Mechanism: Block Receptor and Deliver Toxic species
4) *Cetuximab:
Antigen: *EGFR Tyrosine Kinase
Use: *Colorectal
Mechanism: Block Receptor
5) *Bevacizumab: Antigen: *VEGF (Reduces Angiogenesis) Use: *Colorectal Cancer Mechanism: Absorb Ligand
___________________
Mechanisms:
1) Recruit immune cells to Trigger
*Antibody-Dependent Cell-Mediated Toxicity (ADCC):
_Rituximab
_Alemtuzumab
2) *Absorb a Ligand for a Receptor:
_Bevacizumab
3) *Block Activation of a Receptor:
_Trastuzumab
_Cetuximab
4) *Deliver a Toxic Species to Cancer Cells:
_Trastuzumab-emtansine
Alemtuzumab
Monoclonal Antibodies
*All Must be Given by Infusion
Can Cause Infusion Reactions:
_Rash, *Edema, *Hypotension, Bronchospasms;
_Rarely, Anaphylaxis
1) *Rituximab:
_Antigen: *CD20
_Use: *B cell Lymphoma
_Mechanism: ADCC
2) *Alemtuzumab:
Antigen: *CD52
Use: *T cell Lymphoma
Mechanism: ADCC
3) *Trastuzumab:
Antigen: *HER-2/Neu Tyrosine Kinase
Use: *Breast Cancer
Mechanism: Block Receptor and Deliver Toxic species
4) *Cetuximab:
Antigen: *EGFR Tyrosine Kinase
Use: *Colorectal
Mechanism: Block Receptor
5) *Bevacizumab: Antigen: *VEGF (Reduces Angiogenesis) Use: *Colorectal Cancer Mechanism: Absorb Ligand
___________________
Mechanisms:
1) Recruit immune cells to Trigger
*Antibody-Dependent Cell-Mediated Toxicity (ADCC):
_Rituximab
_Alemtuzumab
2) *Absorb a Ligand for a Receptor:
_Bevacizumab
3) *Block Activation of a Receptor:
_Trastuzumab
_Cetuximab
4) *Deliver a Toxic Species to Cancer Cells:
_Trastuzumab-emtansine
Trastuzumab
Monoclonal Antibodies
*All Must be Given by Infusion
Can Cause Infusion Reactions:
_Rash, *Edema, *Hypotension, Bronchospasms;
_Rarely, Anaphylaxis
1) *Rituximab:
_Antigen: *CD20
_Use: *B cell Lymphoma
_Mechanism: ADCC
2) *Alemtuzumab:
Antigen: *CD52
Use: *T cell Lymphoma
Mechanism: ADCC
3) *Trastuzumab:
Antigen: *HER-2/Neu Tyrosine Kinase
Use: *Breast Cancer
Mechanism: Block Receptor and Deliver Toxic species
4) *Cetuximab:
Antigen: *EGFR Tyrosine Kinase
Use: *Colorectal
Mechanism: Block Receptor
5) *Bevacizumab: Antigen: *VEGF (Reduces Angiogenesis) Use: *Colorectal Cancer Mechanism: Absorb Ligand
___________________
Mechanisms:
1) Recruit immune cells to Trigger
*Antibody-Dependent Cell-Mediated Toxicity (ADCC):
_Rituximab
_Alemtuzumab
2) *Absorb a Ligand for a Receptor:
_Bevacizumab
3) *Block Activation of a Receptor:
_Trastuzumab
_Cetuximab
4) *Deliver a Toxic Species to Cancer Cells:
_Trastuzumab-emtansine
Cetuximab
Monoclonal Antibodies
*All Must be Given by Infusion
Can Cause Infusion Reactions:
_Rash, *Edema, *Hypotension, Bronchospasms;
_Rarely, Anaphylaxis
1) *Rituximab:
_Antigen: *CD20
_Use: *B cell Lymphoma
_Mechanism: ADCC
2) *Alemtuzumab:
Antigen: *CD52
Use: *T cell Lymphoma
Mechanism: ADCC
3) *Trastuzumab:
Antigen: *HER-2/Neu Tyrosine Kinase
Use: *Breast Cancer
Mechanism: Block Receptor and Deliver Toxic species
4) *Cetuximab:
Antigen: *EGFR Tyrosine Kinase
Use: *Colorectal
Mechanism: Block Receptor
5) *Bevacizumab: Antigen: *VEGF (Reduces Angiogenesis) Use: *Colorectal Cancer Mechanism: Absorb Ligand
___________________
Mechanisms:
1) Recruit immune cells to Trigger
*Antibody-Dependent Cell-Mediated Toxicity (ADCC):
_Rituximab
_Alemtuzumab
2) *Absorb a Ligand for a Receptor:
_Bevacizumab
3) *Block Activation of a Receptor:
_Trastuzumab
_Cetuximab
4) *Deliver a Toxic Species to Cancer Cells:
_Trastuzumab-emtansine
Bevacizumab
Monoclonal Antibodies
*All Must be Given by Infusion
Can Cause Infusion Reactions:
_Rash, *Edema, *Hypotension, Bronchospasms;
_Rarely, Anaphylaxis
1) *Rituximab:
_Antigen: *CD20
_Use: *B cell Lymphoma
_Mechanism: ADCC
2) *Alemtuzumab:
Antigen: *CD52
Use: *T cell Lymphoma
Mechanism: ADCC
3) *Trastuzumab:
Antigen: *HER-2/Neu Tyrosine Kinase
Use: *Breast Cancer
Mechanism: Block Receptor and Deliver Toxic species
4) *Cetuximab:
Antigen: *EGFR Tyrosine Kinase
Use: *Colorectal
Mechanism: Block Receptor
5) *Bevacizumab: Antigen: *VEGF (Reduces Angiogenesis) Use: *Colorectal Cancer Mechanism: Absorb Ligand
___________________
Mechanisms:
1) Recruit immune cells to Trigger
*Antibody-Dependent Cell-Mediated Toxicity (ADCC):
_Rituximab
_Alemtuzumab
2) *Absorb a Ligand for a Receptor:
_Bevacizumab
3) *Block Activation of a Receptor:
_Trastuzumab
_Cetuximab
4) *Deliver a Toxic Species to Cancer Cells:
_Trastuzumab-emtansine
Interleukin-2 (IL-2)
Cytokines:
*Interleukin-2 (IL-2)
Mechanism:
=> *Produces Tumor-Cytolytic Lymphocytes
Uses:
1) *Renal Cell Carcinoma (RCC)
2) *Metastatic Melanoma
Colony Stimulating Factors
Differentiating Agents
(Inducing Differentiation should stop cancer cells from dividing)
Effects: @ Level of Gene Transcription
1) *Colony Stimulating Factors:
Mechanism:
=> Act on Cells @ Various Stages of Hematopoietic Hierarchy
Use:
=> Replenish RBCs suppressed by chemotherapy
2) *Retinoic Acids:
(Vitamin A Derivatives)
_Tretinoin (All trans-retinoic Acid)
_*Accutane
Rarely used, but effective against Acute Pro-Myelocytic Leukemias
(=> Reduce likelihood of transformation into Leukemia)
Accutane
Differentiating Agents
(Inducing Differentiation should stop cancer cells from dividing)
Effects: @ Level of Gene Transcription
1) *Colony Stimulating Factors:
Mechanism:
=> Act on Cells @ Various Stages of Hematopoietic Hierarchy
Use:
=> Replenish RBCs suppressed by chemotherapy
2) *Retinoic Acids:
(Vitamin A Derivatives)
_Tretinoin (All trans-retinoic Acid)
_*Accutane
Rarely used, but effective against Acute Pro-Myelocytic Leukemias
(=> Reduce likelihood of transformation into Leukemia)
Cyclosporine
ImmunoSuppressors
Calcineurin Inhibitors:
1) Cyclosporine
2) Tacrolimus
Mechanism:
1) Blocks Calcineurin;
=> Blocking Cell Proliferation
Uses:
1) Organ Transplant
2) Autoimmune:
Rheumatoid Arthritis
Toxicity:
1) Nephrotoxic
2) CYP450 Drug Interactions
Tacrolimus
ImmunoSuppressors
Calcineurin Inhibitors:
1) Cyclosporine
2) Tacrolimus
Mechanism:
1) Blocks Calcineurin;
=> Blocking Cell Proliferation
Uses:
1) Organ Transplant
2) Autoimmune:
Rheumatoid Arthritis
Toxicity:
1) Nephrotoxic
2) CYP450 Drug Interactions
Sirolimus
Immuno
ImmunoSuppressors
Target of Rapamycin (mTOR) Inhibitors:
_Sirolimus
Mechanism:
1) Inhibits mTOR;
=> Blocking Cell Proliferation
Uses:
1) Transplant Rejection
2) Reduce Proliferation in Stents
Toxicity:
1) CYP450 Drug Interactions
2) Elevated Blood Lipids
3) Risk of Cancer
4) Myelosuppression
5) Risk of Infections
Methotrexate
Immuno
ImmunoSuppressors
Anti-Proliferative Agents: => Anti-Metabolites: 1) Methotrexate (Folate Analog) 2) Azathioprine (Purine Analog) 3) Mycophenolate Mofetil (Purine Analog)
Mechanism:
1) Interfere with Nucleic Acid Synthesis
2) Affects Cellular Immunity More than Humoral
Uses:
1) Organ Transplant: *RENAL
2) Some Autoimmune
Toxicity:
1) Myelosuppression
2) GI: Nausea, Vomiting
Azathioprine
ImmunoSuppressors
Anti-Proliferative Agents: => Anti-Metabolites: 1) Methotrexate (Folate Analog) 2) Azathioprine (Purine Analog) 3) Mycophenolate Mofetil (Purine Analog)
Mechanism:
1) Interfere with Nucleic Acid Synthesis
2) Affects Cellular Immunity More than Humoral
Uses:
1) Organ Transplant: *RENAL
2) Some Autoimmune
Toxicity:
1) Myelosuppression
2) GI: Nausea, Vomiting
Mycophenolate Mofetil
ImmunoSuppressors
Anti-Proliferative Agents: => Anti-Metabolites: 1) Methotrexate (Folate Analog) 2) Azathioprine (Purine Analog) 3) Mycophenolate Mofetil (Purine Analog)
Mechanism:
1) Interfere with Nucleic Acid Synthesis
2) Affects Cellular Immunity More than Humoral
Uses:
1) Organ Transplant: *RENAL
2) Some Autoimmune
Toxicity:
1) Myelosuppression
2) GI: Nausea, Vomiting
Cyclophosphamide
Immuno
ImmunoSuppressors
Alkylating Agents:
1) Nitrogen Mustards:
Cyclophosphamide
Mechanism:
1) Alkylates DNA (Cross-Links)
=> Inhibits DNA Synthesis
2) Humoral Immunity Affected More than Cellular Immunity
Uses:
1) Bone Marrow Transplant
2) Autoimmune
Toxicity:
1) Myelosuppression
2) Secondary Neoplasias
3) Hemorrhagic Cystitis
4) GI: Nausea, Vomiting
Prednisone
ImmunoSuppressors
Corticosteroids (Glucocorticoids):
1) Prednisone
2) Hydrocortisone
3) Dexamethasone
Mechanism:
1) Reduce T Cell Function,
2) Reduce Chemotaxis,
3) Inhibit Production of Inflammatory Mediators
Uses:
1) Autoimmune
2) Inflammatory Diseases
3) Transplant Adjunct
Toxicity: 1) Fat Deposition Changes: _Moon Face, Buffalo Hump 2) Diabetes, Hyperglycemia 3) Psychosis 4) Risk of Infection 5) (Discontinue Slowly to Avoid Adrenal Insufficiency
Hydrocortisone
ImmunoSuppressors
Corticosteroids (Glucocorticoids):
1) Prednisone
2) Hydrocortisone
3) Dexamethasone
Mechanism:
1) Reduce T Cell Function,
2) Reduce Chemotaxis,
3) Inhibit Production of Inflammatory Mediators
Uses:
1) Autoimmune
2) Inflammatory Diseases
3) Transplant Adjunct
Toxicity: 1) Fat Deposition Changes: _Moon Face, Buffalo Hump 2) Diabetes, Hyperglycemia 3) Psychosis 4) Risk of Infection 5) (Discontinue Slowly to Avoid Adrenal Insufficiency
Dexamethasone
ImmunoSuppressors
Corticosteroids (Glucocorticoids):
1) Prednisone
2) Hydrocortisone
3) Dexamethasone
Mechanism:
1) Reduce T Cell Function,
2) Reduce Chemotaxis,
3) Inhibit Production of Inflammatory Mediators
Uses:
1) Autoimmune
2) Inflammatory Diseases
3) Transplant Adjunct
Toxicity: 1) Fat Deposition Changes: _Moon Face, Buffalo Hump 2) Diabetes, Hyperglycemia 3) Psychosis 4) Risk of Infection 5) (Discontinue Slowly to Avoid Adrenal Insufficiency
Rh0 Antibody
ImmunoSuppressors
Uses:
=> Prevents Hemolytic Disease of Rh+ Newborn born to Rh- Mother.
Infliximab
ImmunoSuppressors
Binding Proteins:
1) Infliximab
2) Etanercept
Mechanism:
=> Bind to TNF-Alpha
Uses:
1) Rheumatoid Arthritis
2) Crohn’s Disease
3) Psoriasis
Etanercept
ImmunoSuppressors
Binding Proteins:
1) Infliximab
2) Etanercept
Mechanism:
=> Bind to TNF-Alpha
Uses:
1) Rheumatoid Arthritis
2) Crohn’s Disease
3) Psoriasis
Muromonab-CD3
ImmunoSuppressors
Binding Protein
Use:
=> Renal Transplant
Immune Globulin
ImmunoStimulant
Natural Adjuvant
Mechanism:
(Prepared from pooled plasma)
Uses:
(Various ImmunoDeficiency States,
Agammaglobulinemia)
Thalidomide
ImmunoStimulant
Synthetic
Toxicity:
=> Phocomelia!!
(Absent/Short Limbs)
Interferon Alpha
ImmunoStimulant
Cytokines
Uses:
=> Various Neoplasms:
1) Kaposi’s Sarcoma
2) Hairy Cell Leukemia
Interferon Beta-1b
ImmunoStimulant
Cytokines
Use:
=> Relapsing Multiple Sclerosis
Interleukin-2
Immuno
ImmunoStimulant
Cytokines
Mechanism:
=> Produces Cytolytic Lymphocytes Against Tumor Cells
Uses:
1) Renal Cell Carcinoma (RCC)
2) Metastatic Melanoma
