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Intro to Cancer Pharmacology Flashcards

1
Q

Cell Cycle

A
  • G1: DNA is 2n
  • S-phase: DNA replication, synthesizing two identical replicas of DNA (2n => 4n)
  • G2: DNA is 4n
  • Mitosis: splitting to two single cells (4n => 2n)
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2
Q

Cell-Cycle Specific (CCS) Agents

A
  • Inhibit or kill during a particular phase of cell cycle
  • Schedule dependent - need to maintain a cytotoxic level for enough time to allow a tumor to cycle through
  • More effective against tumors with high growth fractions
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3
Q

Antimetabolites Agents + Phase

A
  • All S phase
  • Folic acid analogs
  • Purine analogs (and related antagonists)
  • Pyrimidine analogs
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4
Q

Antimetabolites Agent Info

A
  • Widely Used
  • MoA: structural analog and antagonists of endogenous biochemicals that inhibit purine/pyrimidine synthesis
  • Transported/metabolized/used in biochemical pathways similar to their analogous biochemical
  • Cell-cycle specific with cytotoxicity present in S-phase (phase with nucleotide production)
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5
Q

Antifolates

A
  • Structural analog of folic acid
  • Folic acid’s active form = tetrahydrofolic acid (TFA)
  • TFA involved in single carbon unit transfers as methyl and in purine/pyrimidine metabolism
  • MoA: inhibits dihydrofolate reductase and antifolate activity, also inhibits 1 carbon transfers associated with certain AA
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6
Q

Antifolate Examples

A
  • Methotrexate
  • Trimetrexate
  • Aminopterin
  • Pemetrexed
  • Pralatexate
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7
Q

Methotrexate Absorption Differences

A
  • Low dose methotrexate enters cells through folate transporters
  • High dose methotrexate enters by passive uptake and folate transporters
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8
Q

Leucovorin Rescue

A
  • Reduced folate derivative used to replenish folate pools in normal cells
  • Enters cells with intact folate transporters
  • Bypasses methotrexate blocked enzyme to replenish folate pool
  • Normal cells only have reduced folate, tumors remain folate starved
  • Made use of 5-FU more efficacious, binds TS more avidly when coadministered
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9
Q

Purine Analogs

A

-MoA: inhibition of enzymes involved in de novo purine nucleotide synthesis

EXAMPLES

  • 6-mercaptopurine (6MP)
  • 6-thioguanine (6TG)
  • Fludarabine monophosphate
  • Cladribine
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10
Q

6MP and 6TG

A
  • Require bioactivation by HGPRT to ultimately form triphosphate metabolite
  • Incorporated into DNA and RNA
  • Inhibit biosynthesis of endogenous purines by inhibiting PRPP amidotransferase
  • Decrease DNA/RNA synthesis
  • Active in S phase
  • Short half life due to excesive metabolism
  • Used in leukmekias (and IBD)
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11
Q

Fludarabine Monophosphate-

A
  • Fludara
  • Requires phosphorylation to be active
  • Inhibits DNA polymerase causing DNA chain termination
  • Incorporated into RNA
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12
Q

Cladribine

A
  • Leustatin
  • Requires phosphorylation to be active
  • Inhibits DNA synthesis and repair
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13
Q

Pyrimidine Analogs

A
  • MoA: inhibits synthesis pyrimidine nucleotides mimicking their structure to inhibit DNA synthesis of RNA synthesis
  • Analogs of thymidine and cytidine and analogs of uracil (latter RNA/DNA synthesis)
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14
Q

Pyrimidine Analog Examples

A
  • 5-FU
  • Capecitabine
  • Cytarabine
  • Gemcitabine
  • Trifluridine and tipiracil (TAS-102)

All are thymidine/cytidine analogs that block DNA synthesis

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15
Q

5-FU

A
  • Requires GPAT and orotate phosphribosyl transferase activity to form FdUMP from 5-FU
  • MoA: F-dUMP binds to thymidine synthase and methylene-tetrahydrofolate to inhibit thymidylate synthase activity and block thymidine production
  • Causes thymidine starvation and inhibition of DNA synthesis
  • 5-FU is also bioactivated to 5-FUTP and incorporated into RNA to interfere with RNA processing
  • 5-FU has a short half life due to extensive metabolism
  • Used in colorectal cancer and solid tumors
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16
Q

Capecitabine

A
  • Xeloda
  • Prodrug requiring carboxylesterase, cytidine deaminase, and thymidine phosphorylase activity to produce active form, 5-FU
  • Hydrolysis to 5-FU by thymidine phosphorylase, present at higher levels in some tumors and leads to concentration in tumors
  • Orally bioavailable by metabolism activity
  • Cytotoxicity similar to 5-FU
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17
Q

Trifluridine and Tipiracil

A
  • TAS-102 (Lonsurf)
  • Fluoropyrimidine analog
  • Made up of trifluridine (fluorinated pyrimidine analog) and tipiracil (inhibitor of thymidine phosphorylase)
  • Trifluridine is inactive in its parent form, inhibits thymidylate synthase
  • Approved for colorectal cancer as second line therapy due to toxicities
  • Dose-limiting toxicity: neutropenia dominant myelosuppression, diarrhea, N/V, fatigue, anorexia
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18
Q

Cytarabine

A
  • ara-C
  • S-phase specific
  • Uses arabinose sugar
  • Bioactivation to araCMP by deoxycytidine kinase to araCTP
  • Inhibits DNA polymerase alpha/beta to block DNA synthesis and repair
  • Short half life due to extensive metabolism
  • Not effective orally, metabolized to ara-uridine in liver
  • Used in hematologic malignancies, acute myelogenous leukemia, and non-Hodgkin’s lymphoma
  • NO SOLID TUMOR ACTIVITY
  • Toxicity: myelosuppression, mucositis, N/V
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19
Q

Gemcitabine

A
  • Structure and mechanism similar to ara-C
  • Rapidly eliminated from the plasma
  • Greater cellular accumulation
  • Use: broader than ara-C, can be used in solid tumors
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20
Q

Antimetabolites DLT

A
  • Methotrexate: myelosuppression and mucositis (oral/intestinal ulcerations)
  • 6MP: myelosuppression, mucositis, gastrointestinal distress, hepatotoxicity
  • 5-FU: myelosuppression, mucositis, GI distress, hand-foot syndrome, neurotoxicity
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21
Q

Hydroxyurea

A
  • Inhibits ribonucleotide reductase
  • Used in treatment of polycythemia vera (myeloproliferative neoplasm), CML, and myeloid metaplasia
  • Debatable antimetabolite
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22
Q

Antimitotic Agents + Phases

A
  • All M-phase
  • Taxanes
  • Vinca alkaloids
  • Antimicrotubule inhibitors
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23
Q

Antimitotic Agents + Microtubules

A
  • Active on microtubules and associated cellular structures
  • Microtubules maintain cell shape, localize organelles, and are used for transport, secretion, and mitosis
  • Active in M phase due to microtubule importance in formation of mitotic spindle in mitosis
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24
Q

Vinca Alkaloids

A
  • MoA: bind to tubulin preventing the formation of microtubules by inhibiting tubulin polymerization
  • Vincristine has higher affinity for axonal microtubules and therefore greater neurotoxicity
  • Toxicity: myelosuppression (VB>VC), neurotoxicity (VC), N/V, and alopecia (VB)
25
Q

Vinca Alkaloids Examples

A
  • Vincristine: hematologic cancers, some solid tumor use
  • Vinblastine: use in lymphomas and solid tumors
  • Vinorelbine: semisynthetic derivative of vinblastine, used in NSCLC, breast, and ovarian cancer
26
Q

Taxanes

A
  • MoA: taxanes act by binding to microtubules to promote tubulin polymerization which producing aberrant structures that inhibit mitosis and cell division
  • Use: solid tumors
  • Resistance: p-glycoprotein
  • Toxicity: myelosuppression, neurotoxicity, ocular/visual disturbances, alopecia, asthenia, fatigue, weakness, allergic reaction, cardiac toxicity
27
Q

Taxane Examples

A
  • Paclitaxel
  • Albumin-bound paclitaxel
  • Docetaxel
  • Cabazitaxel
28
Q

Antimicrotubule Inhibitors

A
  • NOT TAXANES
  • Active in M-phase
  • EX: Ixabepilone and Eribulin
29
Q

Ixabepilone

A
  • Ixempra
  • Semisynthetic derivative of epothilone B
  • MoA: binds directly to B-tubulin subunits of microtubules leading to inhibition of normal microtubule dynamics
  • Useful in drug resistant tumors that overexpress P-glycoprotein
  • Administered IV
30
Q

Eribulin

A
  • Halaven
  • Synthetic analog of halichondrin B
  • Moa: Inhibits microtubular growth by sequestering tubulin into nonproductive aggregates
  • Active in some taxane resistant tumors
  • Administered IV
31
Q

Topoisomerase Inhibitors

A
  • MoA: inhibit topoisomerase leading to inhibition of DNA replication and transcription
  • Prevents DNA unwinding, cutting of DNA strands, and inducing DNA strand breakage
32
Q

Topoisomerase I Inhibitors

A
  • S-phase
  • Irinotecan, topotecan, and liposome encapsulated irinotecan
  • Irinotecan is a prodrug needing metabolic activation by SN-38
  • MoA: cause topoisomerase I to become covalently bound to DNA and induces single strand breakage by inhibiting DNA
  • Toxicity: myelosuppression, diarrhea, vomiting
33
Q

Topoisomerase I Uses

A
  • Irinotecan: colorectal and lung cancer
  • Topotecan: ovarian and cervical cancer
  • Both have solid tumor use
34
Q

Topoisomerase II Inhibitors

A
  • G1 - S phase
  • EX: Etoposide and teniposide
  • Inhibit topoisomerase II leading to double strand breaks (S-G2 phase)
  • Both used in hematologic malignancies and solid tumors
  • Toxicity: myelosuppression, alopecia, diarrhea, and N/V
35
Q

CCS Antitumor Antibiotics

A
  • Bleomycin (Blenoxane)
  • Small peptide that binds DNA and chelates iron
  • Acts in G2 phase
  • MoA: binds DNA and causes free radical formation that causes DNA breakage and synthesis inhibition
  • Uses: Hodgkin and non-Hodgkin lymphomas, germ cell cancers, head/neck cancer, squamous cell carcinoma
  • Toxicity: pulmonary, (pneumonitis with cough), can be fatal
36
Q

CCNS Agents

A
  • Affects both cycling and resting cells as well as rapidly dividing cells
  • Uses: lymphatic and solid tumors
  • Agents are carcinogenic themselves with increased risk of secondary cancers
37
Q

CCNS Classes

A
  • Antitumor Antibiotics
  • Alkylating Agents
  • Platinum coordinate complexes
  • Anthracyclines
38
Q

Mitomycin C

A

Mutamycin

  • CCNS Antitumor Antibiotic
  • Requires bioactivation producing alkylating agent that cross-links DNA
  • Useful under hypoxic conditions (solid tumors)
  • Toxicity: Hemolytic-uremic syndrome, microangiopathic hemolytic anemia, thrombocytopenia, and renal failure
39
Q

Dactinomycin

A
  • Cosmegen
  • CCNS Antitumor Antibiotic
  • Actinomycin D
  • Intercalates into DNA; blocks RNA and protein synthesis
  • Induces single-stranded breaks act on topoisomerase II
  • Uses: Wilms tumor, rhabdomyosarcoma, germ cell tumors, Ewing’s sarcoma
40
Q

Alkylating Agents

A
  • MoA: alkylation of DNA produces cross-linking of DNA and DNA strand breakage, miscoding by errant basepairing of guanine with thymine or depurination, repair and strand separation prevention
  • Carcinogenic in nature, increases risk of secondary malignancy
  • Uses: lymphatic and solid cancers
41
Q

Nitrogen Mustard Examples

A
  • Cyclophosphamide
  • Mechorethamine
  • Chlorambucil/Bendamustine
  • Ifosfamide
  • Melphalan
42
Q

Cyclophosphamide

A
  • Cytoxan, Neosar
  • Widely used antineoplastic
  • Activated by P-450 enzymes
  • Orally available
  • Used: breast cancer, non-Hodgkin’s lymphoma, CLL, neuroblastom, Wilm’s tumor, rhabdomyosarcoa
  • Toxicity: myelosuppression, N/V, diarrhea, loss of fertility, cardiac toxicity
  • Can be used with Mesna to reduce Acrolein related toxicity
43
Q

Mechlorethamine

A
  • Mustargen
  • Alkylates guanine; produces DNA cross-links and strand breakage
  • Administered IV
  • Uses: Hodgkin and non-Hodgkin’s lymphoma
  • Can induce blistering
44
Q

Chlorambucil and Bendamustine

A
  • Leukeran and Treanda
  • Some selectively toxic for lymphocytes
  • Uses: CLL and non-Hodgkin lymphoma
45
Q

Nitrosoureas

A
  • Require biotransformation for activity through non-enzymatic decomposition
  • All lipid soluble and cross the BBB
  • N/V major toxicity in all of these agents
46
Q

Nitrosoureas Examples

A
  • Carmustine and Lomustine
  • Alkylation of N7 and O6 on guanine, can produce G-C cross links
  • Toxicity: myelosuppression, renal toxicity, secondary malignancy
47
Q

Alkylsulfonate

A
  • Busulfan
  • Produces carbonium ions that crosslink DNA
  • Uses: CML
  • Toxicity: skin pigmentation, pulmonary fibrosis, adrenal insufficiency
  • N/V!!!!
48
Q

Aziridines

A
  • Thiotepa
  • Uses: breast cancer, ovarian cancer, bladder cancer
  • N/V!!!!
49
Q

Non-classical Alkylating Agents

A
  • MoA: methylated DNA and inhibit DNA synthesis and function
  • Temozolomide: brain cancer, melanoma (N/V, myelosuppression)
  • Procarbazine: inhibits methylation of methionine, used in Hodgkin’s and non-Hodgkin’s lymphoma, and brain cancer (CNS depression)
  • Dacarbazine: Binds to N7 and O6 of guanine, used in Hodgkin’s lymphoma, melanoma, soft tissue carcinoma (N/V, myelosuppression)
50
Q

Platinum Coordinating Agents

A
  • Active in all stages of cell cycle
  • Chloride ion replaced with water to produce reactive intermediate that forms covalent platinum-nitrogen bond at N7 of guanines
  • Produces intra- and inter-strand DNA crosslinks
  • MoA: Inhibition of DNA replication and RNA transcription
  • EX: Cisplatin, Carboplatin, and Oxaliplatin
51
Q

Cisplatin

A
  • Platinol
  • Inorganic complex of platinum and chloride ions
  • Used in breast cancer, lung cancer, bladder cancer, gastroesophageal cancer, ovarian cancer, and germ cell cancer
  • Toxicity: N/V, nephrotoxicity, neuropathy, ototoxicity, and nerve dysfunction
52
Q

Carboplatin

A
  • Paraplatin
  • Second generation platinum analog
  • Less renal and GI toxicity compared to cisplatin
53
Q

Oxaliplatin

A
  • Eloxatin
  • Third generation platinum analog
  • Use in resistant cancers due to mismatch repair defects (metastatic colorectal cancer)
  • Neurotoxic
54
Q

Anthracyclines

A

Exert cytotoxic action though four major mechanisms:

  • High affinity binding to DNA and blocking DNA/RNA synthesis and DNA strand scission
  • Inhibition of topoisomerase II
  • Generation of free radicals
  • Binding to cellular membranes to alter fluidity and ion transport
  • All IV
  • Toxicity: cardiotoxicity (radicals), myelosuppression, and mucositis
55
Q

Anthracycline Examples

A
  • Doxorubicin (Adriamycin): breast, endometrium, ovarian, testicular, thyroid, stomach cancer, etc.
  • Daunorubicin: limited use, not solid tumors, acute myeloid leukemia available as liposomal formulation
  • Idarubicin: acute myeloid leukemia in combination with cytarabine
  • Epirubicin: breast and gastroesophageal cancer
  • Mitoxantrone: castration resistant prostate cancer, non-Hodgkin’s lymphoma, (blue discoloration)
56
Q

Steroid Hormones

A
  • Dexamethasone, prednisone, methylprednisolone
  • Anti-inflammatory activity
  • Dexamethasone used in treatment of multiple myeloma
57
Q

Asparaginase/PEG Asparaginase

A
  • Hydrolyzes circulating asparagine

- Used to treat acute lymphoblastic leukemia

58
Q

Arsenic Trioxide (ATO)

A
  • Used in treatment of refractory promyelocytic leukemia (M3)
  • MoA: uncertain, may involve differentiation
59
Q

Tretinoin

A
  • All-trans retinoic acid (ATRA)
  • Binds and activates the retinoic acid receptor
  • Chromosomally translocated in most acute promyelocytic leukemias

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