Block 4: Chemotherapy
Terms
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- Cell Stages
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G1: RNA and protein synthesis
S: Chromosome replication
G2: rapid growth
M: mitosis
Go: resting phase - Class 1 agents
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All cells killed regardless of state of proliferation
e.g. nitrogen mustard, non-specific alkylating agents - Class 2 agents
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Cell cycle specific
(*the plateau of its curve represents porportion of cells which have not passed through the sensitive phase)
e.g. vinblastine, methotrexate - Class 3 agents
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non-cycle specific-more effective against dividing cells
e.g. cyclophosphamide and daunorubicin - What about a survival curve?
- They're logirithmic--a given dose kills a constant fraction of cells
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In addition to [] dependence what else is a critical factor.
[]= concentration - Time of exposure to lethal []
- Factors affecting chemotherapy
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1. Cell cycle kinetics
2. Growth fraction
3. Tumor heterogenicity
4. Tumor size
5. Tumor resistance - Mechanisms of resistance to chemo drugs.
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1. Transport defects
2. Somatic mutation (6-thioguanine)
3. Gene amplification (methotrexate)
4. MDR - Multidrug resistance
- Overproduction of membrane glycoproteins that actively pump out drugs.
- 5 classes of chemo drugs
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I. Alkylating agents- covalently modify DNA
II Natural Products-block/disrupt biochemistry
III Antimetabolites- mimic
IV Enzymes- degradation
V Biological Response Modifiers (BRM)- growth dependent factors - 5 principal classes of alkylating agents
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1. Nitrogen mustards
2. Ethylenimines
3. Alkylsulfonates
4. Nitrosoureas
5. Triazene - What group do the N-mustards use
- Bis-(2-chloroethyl) group
- MOA of N-mustards
- Alkylate DNA at N-7 of guanine --> breaks and mistakes
- Melphalan (Admin/structure/t1/2, PK)
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Admin: orally
Structure: derivative of phenylalanine
t1/2: 1.5-2.0 hours
PK: Cellular entry by active transports. Alkylating agent. Excreted in stool and some in urine - Chlorambucil
- Alkylating agent similar to melphalan
- How does the liver play a role in Cyclophosphamide activation
- Converts drug into inactive metabolites so that the hepatotoxicity (and other SEs) of nitrogen mustards is reduced or eliminated
- Toxicities of Cyclophosphamide
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Immunosuppression
Nausea
Vomiting
Cystitis
H20 retention
Alopecia
Carcinogenesis - Ifosfamide: Use and SE
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Alkylating agent cyclophosphamide derivative used for testicular cancer
Myelosuppression and urotoxicity - Ethylenimines example-use
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Thiotepa
Breast and ovarian cancer - Ex. of an alkylsulfonate
- Bulsulfan- a bifunctional methanesulfonate
- MOA and PK of Busulfan
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MA: Alkylation via methanesulfonate release
PK: Oral admin, rapid absorption, excreted as methanesulfonic acid - Toxicity of Busulfan
- Myelosuppression (esp. granulocytopenia), increase pigmentation, pulmonary fibrosis
- List the chloroethyl nitrosoureas
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BCNU (carmustine)
CCNU (lomustine)
Methyl CCNU (semustine) - What are the chloroethyl nitrosoureas capable of?
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Alkylation
DNA crosslinking
Carbamoylation of proteins - What gives the chloroethyl nitrosoureas their long t1/2.
- They're lipid soluble (that means the cross the BBB too)
- Carmustine has an intresting adminstration? What is it, how do you use it?
- Given via an implantable water wafer for malignant glioma.
- Toxicities of Chloroethyl nitrosoureas:
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Delayed but severe hematopoietic depression
Pulmonary fibrosis
Renal insufficiency
Alopecia
Nausea
Vomiting - Name a methylnitrosourea. What's its use?
- Streptozocin~ preferentially acts on pancreatic islet cells
- Name 2 Triazenes
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Dacarbazine (DTIC)
Temozolomide - DTIC MOA
- (-) RNA and protein synthesis--> DNA synthesis because of non-specific alkylation
- Toxicities of DTIC
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Nausea
Vomiting
Mild myelosuppression - Use and SE of Temozolomide
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Used for Anaplastic Astrocytoma
SE: Myelosuppression - Cisplatin (Platinol) contains what? What form is active. Use.
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Platinum
Cis-dichloro form
Testicular cancer, ovarian carcinoma, H & N cancers - MOA of Cisplatin
- Alkylation achieved by dissocation of Cl-. Crosslinks are then formed (DNA-DNA, DNA-protein)
- Pharmacology of Cisplatin
- Free platinol cleared by kidneys quickly, but Pt is bound to plasma protein for days; it is inactive
- Cisplatin analogue are
- Cross-resistant
- Toxicities of Cisplatin
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Myelosuppression
Nephrotoxicity
Ototoxicity - How do we attenuate the nephrotoxicity caused by Cisplatin
- Admin sulfhydryl- containing free radical scavenger, Amifostine
- Carboplatin
- Also a platinol analogue but has substantially less renal toxicity, still causes leukopenia and thromobocytopenia
- Procarbazine- use and toxicity
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Non-specific alkylator
Used for Hodgkin's dz
Myelosuppression, carcinogenicity, toxicity w/MAOIs