Anti-Neoplastic Drugs

Front 1

Cancer stats

Back 1

25% of all deaths are due to cancer, 33% will develop cancer; early stage cancers are more curable than late-stage cancers with the first treatment more effective than the next

Front 2

Anti-neoplastic drug reasoning

Back 2

1. Kill all tumor cells 2 suppress the growth of tumor but not normal cells 3 increase the host capacity to fight cancer

Front 3

Ideal Anti-Neoplastic Drug

Back 3

non-toxic to normal cells; kill all tumor cells; broad spectrum of activity; good distribution in body; non-immunogenic; low incidence of side effects; low cost, oral dosing; All drugs fall short

Front 4

What drugs are a High risk for causing 2ndary malignancies

Back 4

Mechlorethamine, carmustine, etoposide (many crazy examples)

Front 5

What drugs are a Moderate risk for causing 2ndary malignancies

Back 5

Doxorubicin, cyclophosphamide, procarbazine, cisplatin

Front 6

What drugs are a Low risk for causing 2ndary malignancies

Back 6

Vincristine, vinblastine, methotrexate, cytarabine, 5-fluorouracil

Front 7

What type of drugs affect the S phase cycle?

Back 7

Antimetabolites and Etoposide (also effects G2); Cytarabine, Fluorouracil, Methotrexate, Mercaptipurine, Hydroxyurea

Front 8

What type of drugs affect the G2 phase cycle?

Back 8

Bleomycin and Etoposide (also S phase), and Placlitaxel

Front 9

What type of drugs affect mitosis?

Back 9

Vinca alkaloids and taxols; Vinblastine and vincristine

Front 10

Cancer Stem Cells

Back 10

Mech of drug resistance; resistant to chemotherapy and radiation; can regenerate tumors; an important reason for therapeutic failure/recurrence

Front 11

Tumor Growth Rate

Back 11

Tumor growth rate decreases with time; actively growing tumor cells are generally more sensitive to chemotherapeutic agents

Front 12

Killing a tumor follows what kind of kinetics?

Back 12

First order; a constant dose of drug kills a constant fraction of tumor cells; tumor size does not predict dose but duration of therapy; log kill best applies to early stages of tumor growth

Front 13

Class I: cell cycle-nonspecific drugs

Back 13

Alkylating agents: Exert cytotoxicity in a nonspecific manner; kill cells in any stage of cell cycle, even Go; kill normal and neoplastic cells to the same extent; AGENTS: MECHLORETHAMINE AND CARMUSTINE

Front 14

What type of drugs affect the G1 phase?

Back 14

Prednisone

Front 15

Class III: Cell cycle specific, Phase Nonspecific Drugs

Back 15

Alkylating Agent-Cyclophosphamide; Metal salf-Cisplatin, Antibiotic-Doxorubicin

Front 16

5-Fluorouracil

Back 16

Inhibits TMP synthesis

Front 17

put more drugs in?

Back 17

?later

Front 18

Alkylating Agents Mechanism

Back 18

Introduce alkyl groups into DNA, RNA, and/or proteins; DNA is likely the most important target; Cause DNA crosslinks, strand breaks, and misreading of code; tend to kill tumor and normal cells equally

Front 19

Cell Cycle nonspecific alkylating agents

Back 19

mechlorethamine, carmustine

Front 20

cell cycle specific phase nonspecific

Back 20

Cyclephosphamide

Front 21

Alkylating agents side effects

Back 21

Hematopoiesis suppression; GI effects-damage to intestinal mucosa, nausea and vomiting; Alopecia (baldness)-"typical" effects are common to many antineoplastics

Front 22

Mechlorethamine

Back 22

Alkylating agents;Nitrogen mustard; cell cycle nonspecific; Combo therapy for Hodgkin's and non-Hodgkin's lymphoma; Bifunctional alkylating agent-produces DNA cross links and highly reactive, disappears from blood in sec to minutes; given IV

Front 23

Cyclophosphamide

Back 23

Oral or Parenteral; Poor penetration into CNS; Cycle-specific phase-nonspecific; PRODRUG activated by liver cytochrome P450s; phosphoramide mustard; bladder toxicity-sterile hemorrhagic cystitis; VERY broad spectrum of activity-used against a wide variety of cancers

Front 24

Carmustine

Back 24

Cycle-nonspecific; Cross the blood-brain barrier very well; Tx) of brain tumors, multiple myeloma, and melanoma; similar toxicity profile

Front 25

Antimetabolites

Back 25

Structural analogs of compounds required for intermediary metabolism; Greatest effectiveness in tumors where cell proliferation in rapid; S-phase specific

Front 26

Methotrexate (MTX) mechanism

Back 26

Binds to dihydrofolate reductase and prevents formation of tetrahydrofolate; cancer cells polymerize methotrexate more than normal cells

Front 27

Leucovorin

Back 27

Helps "rescue" host cells from high doses of methotrexate

Front 28

Methotrexate SE and indications

Back 28

Antimetabolite; Intestinal epithelium damage; bone marrow suppression; renal tubular necrosis; displaces other drugs from serum albumin; Acute lymphocytic leukemia; Choriocarcinoma

Front 29

Fluorouracil mech

Back 29

Antimetabolite; Activated in cells to FUTP which inhibits RNA synthesis and to FdUMP which interferes with thymidylate synthase and ultimately DNA synthesis

Front 30

Fluorouracil SE and uses

Back 30

Antimetabolite; SE: nauseam anorexia, diarrhea; myelosuppression; Broad spectrum of uses: stomach, COLON, pancreas, ovary, head/neck, BREAST, bladder, basal cell carcinoma

Front 31

Cytarabine mech

Back 31

Antimetabolite; Pyrimidine analog that competes for phosphorylation of cytidine; competes for incorporation into DNA and causes chain termination

Front 32

Cytarabine SE and uses

Back 32

Antimetabolite; Marked myelosuppresion (dose limiting); Neurotoxicity; For acute leukemias (acute myelocytic leukemia)

Front 33

Mercaptopurine mech SE and uses

Back 33

Antimetabolite; Purine analog; converted in cells to ribonucleotide that inhibits RNA and DNA synthesis; Side Effects: Bone marrow depression; vomiting, nausea, anorexia, jaundice; Used for Acute leukemia

Front 34

Hydroxyurea

Back 34

Antimetabolite; Inhibits ribonucleotide reductase-blocks conversion of ribonucleotides to dNTPs, thereby preventing DNA synthesis; arrests cells at G1-S interface; Useful in conjunction with radiation; USE-Granulocytic leukemia; SE-hematopoietic depression, GI disturbances

Front 35

Vinca Alkaloids

Back 35

Binds to tubulin, inhibiting proper formation of microtubules and mitotic spindle; Vincristine versus vinblastine-different toxicities and different antitumor spectrum

Front 36

Vinblastine

Back 36

Strongly myelosippressie (Dose-limiting): Epithelial ulcerations Tx)Lymmphomas and breast cancer

Front 37

Vincristine

Back 37

Significantly less bone marrow toxicity-alopecia,neuromuscular abnormalities (incl. peripheral neuropathy) Tx) acute lymphocytic leukemia, lymphomas, Wilm's tumor, neuroblastoma

Front 38

Taxanes

Back 38

Mech: enhances assemble and stability of microtubules by binding to B-subunit of tubulin; different binding site than vinca alkaloids; blocks late in G2 pahse

Front 39

Paclitaxel

Back 39

Taxanes; Useful for refractory ovarian cancer; breast cancer; Can interfere with DNA repair, intensifiying the effects of DNA damage by cisplatin or cyclophosphamide; SE dose-limiting leukopenia, peripheral neuropathy. myalgia/arthralgia

Front 40

Doxorubicin

Back 40

Antitumor antibiotic; cycle-specific phase non-specific; among the most active antitumor agents; wide spectrum of activity; the most widely prescribed agent of this class; lymphomas, breast, ovary, small cell lung

Front 41

Doxorubicin mech

Back 41

intercalates in DNA, distorting DNA helix, causes lipid peroxidation and free radical generation, binds to DNA + topoisomerase II

Front 42

Doxorubicin SE

Back 42

Cardiomyopathy, bone marrow depression, alopecia, GI problems

Front 43

Bleomycin

Back 43

Mixture of iron-containing glycopeptides that bind to DNA; Causis oxidative-like damage to DNA which leads to DNA strand breaks; G2 phase specific; tx) germ cell tumors of testes and ovaries, head, neck, lung, lymphomas

Front 44

Bleomycin SE

Back 44

minimal myelosuppression; pulmonary toxicity (pneumonitis, fibrosis), skin vesiculation, hyperpigmentation

Front 45

Etoposide

Back 45

Mech: Irreversible stabilizes DNA-topoisomerase II complexes; This results in dsDNA breaks that cannot be repaired; Late G2 phase; Tx) Lymphomas, acute leukemia, small cell lung, testis; SE) leukopenia (dose-limiting), nausea, vomiting, diarrhea, alopecia

Front 46

Biological response modifiers

Back 46

Naturally occurring proteins or therapeutic molecules designed to mimic or impact natural proteins; less possibility for serious toxicity

Front 47

Filgrastim

Back 47

Granulocyte colony stimulating factor; goal is to limit chemotherapy-induced neutropenia; promotes progenitors of neutrophils; expands the absolute population of neutrophils providing for quicker recovery from bone marrow suppression; SE bone pain

Front 48

Trastuzumab

Back 48

Mech: monoclonal antibody that binds to HER2 receptor; Tx) 25-30% of metastatic breast cancers that overexpress HER2; SE Cardiomyopathy, hypersensitivity, and infusion rxns (fever, chills)

Front 49

Cisplatin

Back 49

Mech: platinum coordination complex; hydrolysis yields activated species which causes DNA crosslinks; promotes apoptosis; Cycle-specific phase nonspecific; wide antitumor spectrum; Tx) Testicular cancer, ovarian cancer, head, neck, bladder, small cell lung, colon esophagus

Front 50

Cisplatin SE

Back 50

Nephrotoxicity, ototoxicity, peripheral neuropathy, electrolyte disturbances, nausea, vomiting, myelosuppression

Front 51

Procarbazine

Back 51

Mech: activated in vivo by liver enzymes to a methylating agent which causes chromosomal damage; an atypical alkylating agent (non x-resistance with other alkylating agents); Tx) Hodgkin's lymphoma; SE-myelosuppression, nausea, vomiting

Front 52

Hormones and hormone antagonists

Back 52

Useful against tumors that are steroid hormone-dependent; 33% of all breast cancers respond to hormonal therapy; 66% of breast cancers with good estrogen receptor content respond to hormonal therapy

Front 53

Possible stratagies for hormonal therapy

Back 53

"opposite" steroidal compounds (ex androgens for breast cancer); anti-hormonal compounds;

Front 54

Prednisone

Back 54

Binds to steroid receptors may arrest cells at G1; depress expression of many growth related genes; induce nucleases which may modulate cell lysis; lympholytic for lymphona and leukemia, also used for breast cancer; SE-immunosuppression; good for combo therapy

Front 55

Tamoxifen

Back 55

Nonsteroidal antiestrogen that competitively blocks estrogen receptors in breast tissue; generally cytostatic; tumor regrows when tamoxifen removed; stopping cell growth without necessarily killing the cells; Tx) advanced post-menopausal breast cancer, pre menopausal metastatic breast cancer and breast cancer prophylaxis for women at high risk

Front 56

What is Tamoxifen activated by?

Back 56

CYP2D6

Front 57

Tamoxifen and letrozole SE

Back 57

Nausea, hot flashes, fatigue, bone and other musculoskeletal pain

Front 58

Aromatase

Back 58

The major way of generating estrogen in post-menopausal women

Front 59

Letrozole

Back 59

Mech: Block conversion of androgens to estrogens by inhibiting aromatase; bind irreversibly to the heme of CYP19; Tx) 1st line tx of post menopausal advanced or metastatic breast cancer;

Front 60

Letrozole time to progression and objective response rate

Back 60

9.4 months and 32% objective rate

Front 61

Letrozole vs Tamoxifen SE

Back 61

Tamoxifen increases bone density while aromatase inhibitors have been associated with decreased bone mineral density

Front 62

Leuprolide

Back 62

Mech: analog of GnRH, after 2-4 weeks, it desensitizes GnRH signaling, decreasing LH/FSH and decreasing testosterone to castration levels; Tx) advanced hormonally responsive prostate cancer; SE Hot flashes and impotence

Front 63

Flutamide

Back 63

Nonsteroidal antiandrogen that blocks androgen receptors; Tx) of metastatic prostate cancer; SE: gynecomastia, diarrhea, hepatotoxicity

Front 64

Resistance to anti-neoplastics

Back 64

Most tumors will contain a small fraction that are likely resistant to one drug (and related drugs); combination therapy is a key strategy in overcoming resistance

Front 65

Multi-drug resistance

Back 65

Mediated by ATP dependent drug efflux pumps that can cause simultaneous resistance to many drugs; especially prominent for vincristine and vinblastine, doxorubicin, bleomycin, etoposide, paclitaxel

Front 66

Principles of combination chemotherapy

Back 66

Different cell cycle specificities, active as single agents, non-overlapping toxicities, different mechanisms of action

Front 67

Sequential blockade

Back 67

Simultaneous action of two inhibitors acting on different steps of a linear metabolic pathway; ex) methotrexat and 5-FU

Front 68

Concurrent Inhibition

Back 68

Inhibitors block two separate pathways that lead to the same end product

Front 69

Complementary inhibition

Back 69

One drug affects the function of an end product, the other drug affects the synthesis of that end product (ex. cytarabine and doxorubicin-inhibit DNA synthesis and causes DNA damage respectively)

Front 70

Synchronization

Back 70

Synchronize cells so they are in one phase and then use a drug that is specific for that phase; low doses of fluorouracil to block in S phase; then high dose of Cytarabine to kill in S phase

Front 71

Recruitment

Back 71

Bring cells out of Go and back into cell cycle; therapy with cell cycle-nonspecific drugs (mechlorethamine or carmustine)