Chemotherapy Drugs Flashcards by Deana Cairo

What are the two classes of alkylating agent?

Nitrogen Mustards
Platinum Analogs

(Also: nitrosoureas and alkylsulfonates, but these weren’t discussed)

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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

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Clinical indications of Cyclophosphamide

Lymphomas
Leukemias
Multiple Myeloma
Breast and Ovarian Carcinoma
Small Cell Lung Cancer
Some Autoimmune Conditions

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What prevents hemorrhagic cystitis that is a side effect of cyclophosphamide?

MESNA: mecaptoethane sulfonate

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Clinical Indications of Cisplatin

Testicular, Ovarian, Bladder, Non-Small and Small Cell Lung Cancers

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Cisplatin has prominent activity during which phase of the cell cycle?

S phase

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Toxicities of Cisplatin

Dose-limiting toxicity is cumulateive, leading to irreversible damage to the renal tubules (prevented with mannitol)
Ototoxic with tinnitus, hearing loss

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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

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What are the three subclasses of antimetabolites?

Folic Acid Analogs
Purine Analogs
Pyrimidine Analogs

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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

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Renal excretion of MTX is inhibited when it interacts with…

Penicillin
Cephalosporins
NSAIDs

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What drug is used in combo with MTX as a rescue drug?

Leucovorin: rescues normal cells from toxicity

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6-MP and 6-TG are metabolized by ____ to active metabolites ____ and ____

HGPRT
TIMP
TGMP

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Clinical Uses of 6-MP and 6-TG

6-MP: ALL, AML, Crohn’s

6-TG: AML

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The purpose of allopurinol with 6-MP use

Prevents hyperuricemia by inhibiting 6-MP metabolism by xanthine oxidace

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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

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Uses for 5-FU

Colon cancer (5-FdUMP), breast, gastroesophageal, hepatocellular, pancreatic cancer

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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

1. Primary: tumor cells don't respond to initial chemotherapy 2. Acquired: develops as a consequence of chemotherapy

Examples of Drug Resistance

1. Up-regulation of drug resistance transporters 2. Down-regulation of methotrexate transporter 3. Increased expression of DNA repaired enzymes 4. 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

1. Drugs with different mechanism of action should be combined 2. Drugs targeting different populations of cancer cells should be combined CCS with CCNS drugs 3. Drugs with different organ toxicities should be combined, so full/nearly full therapeutic doses can be utilized for each drug 4. Drugs associated with different modes of resistance should be combined to minimize cross-resistance 5. 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