Antineoplastic Agents Flashcards Preview

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Flashcards in Antineoplastic Agents Deck (34)
1

Cyclophosphamide

Alkylating Agent

Bischloroethyl amine

Anti-Tumor, less highly reactive derivative

Alkylating activity requires activation in liver or tumor tissues

Treats autoimmunity as well

2

Mechlorethamine

Alkylating agent

Bischloroethyl amine

Nitrogen mustard (prototype of alkylating agents)

Analog of mustard gas

Highly Reactive DNA alkylating/damaging agent

Necrosis if given as IV administration

A part of the MOPP regiment (Hodgkin's disease) with vincristine, procarbazine, and prednisone

3

Nitrosoureas

Alkylating Agent

Little cross-resistance with other alkylating agents

Crosses blood-brain barrier

Useful against brain tumors

Compare with bichloroethyl amines

4

Procarbazine

Alkylating Agent

Metabolized to alklating and free radical (reacting) intermediate

Effective in MOPP regimen against Hodkin's disease

Little cross-resistance with other antineoplastic agents

Leukemogenic (5-10% risk with MOPP regimen), alternative is ABVD regimen

Highly toxic

5

cisplatin and carboplatin

Platinum Coordination complex

Reacts with DNA causing displacement of helix/cross-linking

Blocks the DNA repair enzyme to fix the DNA damage

2 Chlorides allow cross link to occur

Cell cycle nonspecific, DNA crosslinking

May inhibit DNA biosynthesis

Useful in various combination regimens

Ovarian and testicular cancer

Clinical toxicity: NEPHROTOXIC (hydration) and ACOUSTIC NERVE DYSFUNCTION

6

methotrexate

Anti-tumor Antimetabolite

Folic acid analog

Dihydrofolate reductase inhibitor (DHFR)

Blocks synthesis of DNA, RNA and precursors

Accumulates in cells as Polyglutamate derivative

S phase-specific!!

Structures contains extra methyl that causes disfunction

Mechanisms of Resistance
- Amplification of DHFR gene
- DHFR gene mutation
- Decreased uptake
- Increased drug efflux

FOLINIC ACID "rescues" aids in bone marrow recovery

7

Leucovorin-folinic Acid Rescue

Rescues body from methotrexate toxicity by aiding in bone marrow recovery,

Cycled after methotrexate use

8

Fluorouracil (5-FU)

Pyrimidine Antagonist

Metabolite Fluorodeoxyuridine monophosphate (FdUMP) inhibits thymidylate synthetase-- THYMINELESS DEATH

Metabolites incorporated into newly synthesized DNA and RNA

S phase-specific

9

capecitabine

Pyrimidine Antagonist

Oral prodrug of fluorouracil

Preferentially activated in tumor tissues (thymidine phosphorylase)

Approved for COLON CANCER and REFRACTORY BREAST CANCER
- Due to tumor cells having a high lvl of thymidine phosphorylase

Enzymes for Metabolism:
- Carboxylesterase
(Capecitabine-- 5-DFCR)
- Cytidine Deaminase
(5-DFCR---5 DFUR)
- Thymidine Phosphorylase
(5-DFUR--5-FU)
- Dihydropyrimidine dehydrogenase

10

Cytarabine (cytosine arabinoside), araC

Pyrimidine Antagonist

Converted into araCMP, then to araCTP

araCTP is an inhibitor of DNA synthesis, also incorporated into DNA leading to mutations/DNA strand breaks

Metabolic activation requires Deoxycytidine kinase

Mutational loss of deoxycytidine kinase: MECHANISM of TUMOR CELL RESISTANCE

11

6-mercaptopurine/

Purine Antagonist

Metabolites inhibit de novo purine synthesis (masquerade as normal base)

Interfere with DNA and RNA synthesis

Fraudulent base incorporation (mismatches, strand breaks)

S-phase specific

Activated by conversion to NMPs, NTPs, via hypoxanthine-guanine phosphoribosyl transferase (HGPRT)

Down regulation of HGPRT: RESISTANCE to MEDICATION

INACTIVATED by xanthine oxidase

LOW BIOAVAILABILITY when administered with Cow's Milk (high xanthine oxidase)

Enhanced with ALLOPURINOL, due to allopurinol inhibiting xanthine oxidase (look to lower dosage)

12

6-thioguanine

Purine Antagonist

Metabolites inhibit de novo purine synthesis (masquerade as normal base)

Interfere with DNA and RNA synthesis

Fraudulent base incorporation (mismatches, strand breaks)

S-phase specific

Activated by conversion to NMPs, NTPs, via hypoxanthine-guanine phosphoribosyl transferase (HGPRT)

Down regulation of HGPRT: RESISTANCE to MEDICATION

13

bleomycin

Anti-tumor Antibiotic

Main cytotoxic action is DNA strand Scission

PULMONARY TOXICITY (pulmonary fibrosis) at large doses

NO significant myelosuppresion (allows in combination regimen (ABVD, (doxorubicin, bleomycin, vinblastine, dacarbazine) in Hodgkin lymphoma

Natural Product: "anaphylatic" reactions, administer small test dose to check first

14

daunorubicin

Anti-tumor antibiotic and Topoisomerase Inhibitor

Anthracyclines

Used with broad spectrum of activity

DNA intercalation (mutagenic, carcinogenic)

DNA topoisomerase II binding, DNA scission

Irreversible cardiac toxicity at HIGH DOSES
- Heart monitoring REQUIRED

15

doxorubicin

Anti-tumor Antibiotic
Anthracycline

Widely used with broad spectrum of activity

DNA intercalation (mutagenic, carcinogenic)

DNA topoisomerase II binding, DNA scission)

IRREVERSIBLE CARDIAC TOXICITY at HIGH DOSES (requires heart monitoring when administered)

Part of ABVD regimen for Hodgkin and other lymphoma

16

paclitaxel

Mitotic Spindle Poison

Plant alkaloid (bark/leaves of Western Yew)

Enhances tubulin polymerization (blocks microtubule disassembly)

Ovarian and Advanced Breast Cancers

Blocks MT disassembly

17

vinblastine

Mitotic Spindle Poison

Vinca Alkaloid

Part of the ABVD regimen in Hodgkins Lymphoma (doxorubicin, Bleomycin, Vinblastine, Dacarbazine)

Cell Cycle Specific (M-phase)

Inhibitor of Microtubule (tubulin) polymerization (mitotic arrest)

Side Effects: Acute nausea, Vomiting and dose-limiting bone marrow depression

Effective against Hodkins and other lymphoma

RESISTANCE by TUBULIN GENE MUTATION (cannot bind)

MYELOBLAST SUPPRESSION!!!!! (side effects)

18

Vincrisitine

Mitotic Spindle Poison

Vinca Alkaloid

Arrests mitosis via binding to microtubules (tubulin)

No acute side effects and milder, non-dose-limiting bone marrow depression, significant neurotoxicity (muscle weakness)

Used for Acute Childhood Leukemia

HODKINS disease (MOPP regimen)

RESISTANCE by TUBULIN GENE MUTATION

NO MYELOSUPPRESSION

Degenerates axons

19

Irinotecan

Topoisomerase Inhibitor

Camptothecins

Binds to the "cleavable complex" of DNA topoisomerase I and DNA, block RELIGATION of single-strand break

Double-strand breaks OCCUR with DNA replication: S PHASE SPECIFIC

Colorectal Cancer

DOSE LIMITING TOXICITY: Severe Diarrhea

20

etoposide

Topoisomerase Inhibitor

Blocks TOPO II

Inhibits binding by forming TENARY COMPLEX with TOPO II

Interferes with RELIGATION of DOUBLE-STRAND BREAK

DNA Strand Scission

Resistance due to:
- MDR1 Drug Transporter

21

Tamoxifen

Antagonist of Hormone Action

Competitive Inhibitor: Estrogen Binding
- Selective estrogen Response Modulator (SERM)

Partial agonist of estrogen receptor

Efficacy depends on estrogen receptor isoform

Low Toxicity, Side Effects are HOT FLASHES

Employed against cancers of Estrogen Responsive Tissues, FEMALE AND MALE BREAST, Uterine ENDOMETRIUM

40% OF BREAST CANCERS are estrogen sensitive

Prophylatic tamoxifen treatment suggested as effective breast cancer prevention in high-risk women

Does not increase life span

Therapy in postmenopausal women reduces risk of bone fractures

INCREASED RISK of THROMBOSIS/EMBOLISM and Endometrial cancer associated with therapy

22

Raloxifene

Antagonist of Hormone Action

Estrogen Receptor Partial Agonist

SERM

Approved for treatment of breast cancer

Best cancer prevention due to limited associated risks of endometrial cancer and thrombotic events (as seen in tamoxifen)

STAR study to see the effectiveness of raloxifene and tamoxifen in breast cancer prevention, showed raloxifene had a lower risk of endometrial cancer and thrombotic

23

anastrozole

Antagonist of Hormone Action

Aromatase Inhibitor

Inhibits conversion of androgens to estrogen

Block estrogen production in postmenopausal women

Not used in premenopausal women because of compensatory gonadotropin and ovarian estrogne production

More effective than Tamoxifen in treatment of Estrogen Receptor sensitive breast cancer

Useful against tamoxifen resistance tumors (second-line therapy) in postmenopausal women

Untoward effects: joint pain, loss of bone density

24

letrozole

Antagonist of Hormone Action

Aromatase Inhibitor

Inhibits conversion of androgens to estrogen

Block estrogen production in postmenopausal women

Not used in premenopausal women because of compensatory gonadotropin and ovarian estrogne production

More effective than Tamoxifen in treatment of Estrogen Receptor sensitive breast cancer

Useful against tamoxifen resistance tumors (second-line therapy) in postmenopausal women

Untoward effects: joint pain, loss of bone density

25

exemestane

Antagonist of Hormone Action

Aromatase Inhibitor

Inhibits conversion of androgens to estrogen

Block estrogen production in postmenopausal women

Not used in premenopausal women because of compensatory gonadotropin and ovarian estrogne production

More effective than Tamoxifen in treatment of Estrogen Receptor sensitive breast cancer

Useful against tamoxifen resistance tumors (second-line therapy) in postmenopausal women

Greatly reduces risk of breast cancer (75%) in high risk POSTMENAPAUSAL WOMEN

Untoward effects: joint pain, loss of bone density

26

leuprolide

Antagonist of hormone action

Anti-androgen therapy

Synthetic peptide of Gonadotropin Releasing Hormone (GnRH, LHRH)
- A GnRH-R agonist

Pulsatile: Delivery elevates levels of androgens in men and women

Continuous, high dose: Lowers androgen levels in men and estrogen levels in post menopausal women
- Chemical Castration, Androgen Ablation

Effective as estrogen therapy
Effective as orchiectomy in Treatment of Prostate Cancer with fewer side effects

27

flutamide

Antagonist of Hormone Action

Androgen Receptor Antagonist

Ineffective alone, due to rapid androgen receptor mutation

Used in conjunction with leupromide to block effets of initial pulse of androgen levels
- Blocks associated flare of prostate cancer therapy

28

prednisone

Adrenocorticosteroid

Anti-inflammation

Induces apoptosis in Leukemia Cells

used in multidrug regimens for leukemia, lymphoma and myeloma

Does not cure leukemias, but useful in inducing remission in acute LYMPHOBLASTIC or underdifferentiated leukemia or childhood

Palliative Agent in other cancers (reduce inflammation and nausea)

29

lapatinib

EGFR (epidermal growth Factor) kinase Inhibitor

HER2 Kinase Inhibitor

Small molecule used in breast cancer clinical trials (HER2+ BC)

30

erlotinib

EGFR (epidermal growth factor) Kinase Inhibitor
= Protein Tyrosine Kinase
- Overexpressed/mutationally activated in various cancers
- Brain, lung, head, and neck cancer

Small molecule EGFR inhibitor that is approved for non-small cell lung cancer (NSCLC) and in clinical trials for head and neck cancers

31

imatinib

Bcr/Abl kinase inhibior
- Arises from a gene rearragnement/fusion in CHRONIC MYLEGENOUS LEUKEMIA

Small molecule inhibitor of ABL protein tyrosine kinase
- Also against PDGFR and kit (stem cell factor receptor) kinases

Approved for:
- CHRONIC MYELOGENOUS LEUKEMIA
- GI stromal tumors (kit)
- chronic myelomonocytic leukemia (ETV6-PDGFR fusion)

32

cetuximab

Chimeric/humanized antibody

Chimeric EGFR (epidermal growth factor) antibody approved for use in COLON CANCER and HEAD AND NECK CANCER

33

trastuzumab

Chimeric/humanized antibody

Humanized antibody

Used for REFRACTORY METASTATIC BREAST CANCER

Recognizes the cell surface antigen HER2/Neu
-DRAMATICALLY elevated in 30% breast tumors

Effective against (HER2) breast tumors

Direct tumor cell effects

Immune system-mediated effects

34

brentuximab vedotin

Chimeric antibody

Target CD30 of Hodgkin and non-Hodgkin lymphoma cells

IgG conjgated to Highly Toxic Mitotic Spindle Poison Vedotin, Cleavable linker

Accellerated FDA approval

Upon binding, CD30-positive tumor cells internalize brentuximab vedotin and proteolytically cleaved to release toxin