Antineoplastic Agents Flashcards
(67 cards)
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.
