Intro to Cancer Pharmacology Flashcards
(59 cards)
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)
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
3
Q
Antimetabolites Agents + Phase
A
- All S phase
- Folic acid analogs
- Purine analogs (and related antagonists)
- Pyrimidine analogs
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)
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
6
Q
Antifolate Examples
A
- Methotrexate
- Trimetrexate
- Aminopterin
- Pemetrexed
- Pralatexate
7
Q
Methotrexate Absorption Differences
A
- Low dose methotrexate enters cells through folate transporters
- High dose methotrexate enters by passive uptake and folate transporters
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
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
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)
11
Q
Fludarabine Monophosphate-
A
- Fludara
- Requires phosphorylation to be active
- Inhibits DNA polymerase causing DNA chain termination
- Incorporated into RNA
12
Q
Cladribine
A
- Leustatin
- Requires phosphorylation to be active
- Inhibits DNA synthesis and repair
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)
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
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
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
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
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
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
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
21
Q
Hydroxyurea
A
- Inhibits ribonucleotide reductase
- Used in treatment of polycythemia vera (myeloproliferative neoplasm), CML, and myeloid metaplasia
- Debatable antimetabolite
22
Q
Antimitotic Agents + Phases
A
- All M-phase
- Taxanes
- Vinca alkaloids
- Antimicrotubule inhibitors
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
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
Vinca Alkaloids Examples
- 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
Taxanes
- 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
Taxane Examples
- Paclitaxel
- Albumin-bound paclitaxel
- Docetaxel
- Cabazitaxel
28
Antimicrotubule Inhibitors
- NOT TAXANES
- Active in M-phase
- EX: Ixabepilone and Eribulin
29
Ixabepilone
- 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
Eribulin
- 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
Topoisomerase Inhibitors
- MoA: inhibit topoisomerase leading to inhibition of DNA replication and transcription
- Prevents DNA unwinding, cutting of DNA strands, and inducing DNA strand breakage
32
Topoisomerase I Inhibitors
- 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
Topoisomerase I Uses
- Irinotecan: colorectal and lung cancer
- Topotecan: ovarian and cervical cancer
- Both have solid tumor use
34
Topoisomerase II Inhibitors
- 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
CCS Antitumor Antibiotics
- 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
CCNS Agents
- 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
CCNS Classes
- Antitumor Antibiotics
- Alkylating Agents
- Platinum coordinate complexes
- Anthracyclines
38
Mitomycin C
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
Dactinomycin
- 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
Alkylating Agents
- 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
Nitrogen Mustard Examples
- Cyclophosphamide
- Mechorethamine
- Chlorambucil/Bendamustine
- Ifosfamide
- Melphalan
42
Cyclophosphamide
- 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
Mechlorethamine
- Mustargen
- Alkylates guanine; produces DNA cross-links and strand breakage
- Administered IV
- Uses: Hodgkin and non-Hodgkin's lymphoma
- Can induce blistering
44
Chlorambucil and Bendamustine
- Leukeran and Treanda
- Some selectively toxic for lymphocytes
- Uses: CLL and non-Hodgkin lymphoma
45
Nitrosoureas
- 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
Nitrosoureas Examples
- Carmustine and Lomustine
- Alkylation of N7 and O6 on guanine, can produce G-C cross links
- Toxicity: myelosuppression, renal toxicity, secondary malignancy
47
Alkylsulfonate
- Busulfan
- Produces carbonium ions that crosslink DNA
- Uses: CML
- Toxicity: skin pigmentation, pulmonary fibrosis, adrenal insufficiency
- N/V!!!!
48
Aziridines
- Thiotepa
- Uses: breast cancer, ovarian cancer, bladder cancer
- N/V!!!!
49
Non-classical Alkylating Agents
- 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
Platinum Coordinating Agents
- 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
Cisplatin
- 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
Carboplatin
- Paraplatin
- Second generation platinum analog
- Less renal and GI toxicity compared to cisplatin
53
Oxaliplatin
- Eloxatin
- Third generation platinum analog
- Use in resistant cancers due to mismatch repair defects (metastatic colorectal cancer)
- Neurotoxic
54
Anthracyclines
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
Anthracycline Examples
- 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
Steroid Hormones
- Dexamethasone, prednisone, methylprednisolone
- Anti-inflammatory activity
- Dexamethasone used in treatment of multiple myeloma
57
Asparaginase/PEG Asparaginase
- Hydrolyzes circulating asparagine
| - Used to treat acute lymphoblastic leukemia
58
Arsenic Trioxide (ATO)
- Used in treatment of refractory promyelocytic leukemia (M3)
- MoA: uncertain, may involve differentiation
59
Tretinoin
- All-trans retinoic acid (ATRA)
- Binds and activates the retinoic acid receptor
- Chromosomally translocated in most acute promyelocytic leukemias
