Chemotherapy Drugs Flashcards
What are the two classes of alkylating agent?
Nitrogen Mustards
Platinum Analogs
(Also: nitrosoureas and alkylsulfonates, but these weren’t discussed)
MOA of Alkylating Agents?
Alkylate DNA at N7 position of guanine…leads to protein miscoding and apoptosis
Can also cause cross-linking of DNA…damaged DNA cannot repair and undergoes apoptosis
Clinical indications of Cyclophosphamide
Lymphomas Leukemias Multiple Myeloma Breast and Ovarian Carcinoma Small Cell Lung Cancer Some Autoimmune Conditions
What prevents hemorrhagic cystitis that is a side effect of cyclophosphamide?
MESNA: mecaptoethane sulfonate
Clinical Indications of Cisplatin
Testicular, Ovarian, Bladder, Non-Small and Small Cell Lung Cancers
Cisplatin has prominent activity during which phase of the cell cycle?
S phase
Toxicities of Cisplatin
- Dose-limiting toxicity is cumulateive, leading to irreversible damage to the renal tubules (prevented with mannitol)
- Ototoxic with tinnitus, hearing loss
Resistance of Alkylating Agents
- Increased DNA repair ability of the tumor cells
- Decreased transport of alkylating drug into cell
- Increased production of glutathione and glutathione-associated proteins
- Increased glutathione S-transferase activity
What are the three subclasses of antimetabolites?
Folic Acid Analogs
Purine Analogs
Pyrimidine Analogs
How does Methotrexate work?
Folic acid analog that binds to the active site of DHFR
Blocks the formation of THF, resulting in interruption in DNA, RNA, and protein synthesis
Renal excretion of MTX is inhibited when it interacts with…
Penicillin
Cephalosporins
NSAIDs
What drug is used in combo with MTX as a rescue drug?
Leucovorin: rescues normal cells from toxicity
6-MP and 6-TG are metabolized by ____ to active metabolites ____ and ____
HGPRT
TIMP
TGMP
Clinical Uses of 6-MP and 6-TG
6-MP: ALL, AML, Crohn’s
6-TG: AML
The purpose of allopurinol with 6-MP use
Prevents hyperuricemia by inhibiting 6-MP metabolism by xanthine oxidace
Mechanism of Action of 5-FU
5-FU gets converted to 5-FUTP, 5-FdUMP, 5-FdUTP
5-FUMP –> RNA damage
5-FdUMP –> DNA damage and inhibits thymidylate synthase
Uses for 5-FU
Colon cancer (5-FdUMP), breast, gastroesophageal, hepatocellular, pancreatic cancer
MOA of vinca alkaloids
Binds to B-tubulin and prevents polymerization
Depolymerization of microtubules blocking mitotic spindle formation during M phase
Mitotic arrest at metaphase interferes with chromosome segregation
Vinblastine: Indications
Hodgkin’s, non-Hodgkin’s
Breast Cancer
Testicular Tumors
Vinblastine Toxicity
Bone marrow suppression, anorexia, N/V/D, alopecia
Vincristine: Indications
Childhood Cancer, Childhood Tumors
Vincristine: Toxicities
Peripheral neuritis/neuropathy with paresthesia, muscle weakness
MARROW SPARING
Etoposide, Teniposide: Indications
Testicular, Non-small and small cell lung carcinomas, AML, ALL, Hodgkin’s and non-Hodgkin’s
Etoposide, Teniposide: MOA
Blocks tumor cells in the late S-G2 phase of cell cycle through inhibition of topoisomerase II
Topotecan and Irinotecan: Indications
Topotecan: Ovarian and small cell lung cancers
Irinotecan: metastatic colon cancer
Camptothecins: MOA
Inhibit topoisomerase I resulting in DNA strand breakage
Doxorubicine: Indications
Hodgkin’s and non-Hodgkin’s, breast, ovarian, bladder cancers, ALL
Doxorubicin is derived from…
Streptomyces
Doxorubicine: MOA
Intercalation interferes with DNA synthesis
Inhibits topoisomerase II leading to DNA fragmentation
Doxorubicine: Toxicities
Reversible acute arrhythmias and conduction abnormalities
Bleomycin: Toxicities
Dose-limiting pulmonary fibrosis that can be fatal
Bleomycin: Indications
Testicular, squamous cell carcinoma, Hodgkin’s and non-Hodgkin’s
Bleomycin: MOA
Intercalation, scission, and fragmentation of DNA due to an oxidation reaction mediated by a DNA-bleomycin-Fe complex
Cancer Treatment Modalities
Surgery Radiotherapy Chemotherapy Endocrine Therapy MAB/Biologics Small Molecule Inhibitors
Log-Kill Hypothesis
Killing action of CCS (cell-cycle specific) drugs follows first order kinetics (a given dose kills a proportion of a cancer cell population
Most solid tumors display what type of pattern?
Gompertzian…growth rates decline as tumor expands
Dose-limiting toxicity
Each cytotoxic drug is associated with a particular organ that effectively limits the max dose of the drug that can be given to a patient
Types of Drug Resistance
- Primary: tumor cells don’t respond to initial chemotherapy
- Acquired: develops as a consequence of chemotherapy
Examples of Drug Resistance
- Up-regulation of drug resistance transporters
- Down-regulation of methotrexate transporter
- Increased expression of DNA repaired enzymes
- Increased expression enzymes that produce trapping metabolites within resistant cells
CSC Theory to Resistance
Anti-cancer treatments can often shrink tumor size by targeting bulk but they fail to target and kill CSCs leading to treatment failure, relapse, and death
Properties of CSCs
Undergo asymmetric cell division: 1 CSC and 1 daughter cell
Resistant to standard chemotherapy
Resistant to radiation (linked to loss of suppressor gene p53)
Principles of Combination Chemotherapy Regimen
- Drugs with different mechanism of action should be combined
- Drugs targeting different populations of cancer cells should be combined CCS with CCNS drugs
- Drugs with different organ toxicities should be combined, so full/nearly full therapeutic doses can be utilized for each drug
- Drugs associated with different modes of resistance should be combined to minimize cross-resistance
- Identify drug combinations that allow for the shortest possible treatment-free period
Rapidly growing tumors are most sensitive to…
CCS chemotherapeutic drugs
CCNS definition
Cell Cycle Non-Specific Drugs
Drugs capable of exerting their actions on cancer cells that are cycling or in the resting state
