Anti-Neoplastics

Question 1

What is the mechanism of Alkylating Agents?

Answer 1

• Introduce alkyl groups in DNA (most important), RNA, and/or proteins.
• Causes DNA crosslinks, strand breaks, code misreading
• Least selective of antineoplastics

Question 2

What is the cell cycle specificity of Alkylating Agents?

Answer 2

• Some cell-cycle nonspecific (also affects G0 cells)
  e. g. mechlorethamine, carmustine
• Some cycle-specific phase-nonspecific (spares G0)
  e. g. cyclophosphamide

Question 3

Name five classes of alkylating agents

Answer 3

• Nitrogen Mustards
• Alkyl Sulfonates
• EthylEnimines/MethylMelamines (E & E, M & M)
• Nitrosoureas
• Triazenes

Question 4

Mechlorethamine

Answer 4

Class: Alkylating Agent (Nitrogen Mustard). Cycle-nonspecific
Use: Prototype - limited use today. Lymphomas (incl. Hodgkin’s), breast, lung, ovarian CA
Kinetics: Gone from blood in seconds to minutes, no CNS penetrance
Route: IV
S/E: N/V, Myelosuppression, mild Alopecia

Question 5

Cyclophosphamide

Answer 5

Class: Alkylating Agent (Nitrogen Mustard). Cycle-specific phase-nonspecific
Use: Broad spectrum. Most used agent in this class
Kinetics: Prodrug, activated by P450s. Poor CNS penetration
Route: Oral or parenteral
S/E: Sterile hemorrhagic cystitis (bladder toxicity), N/V, Alopecia, limited Myelosuppression

Question 6

Mesna

Answer 6

Use: Organosulfur compound given to reduce bladder toxicity from toxic byproducts of cyclophosphamide activation (acrolein)

Question 7

Carmustine

Answer 7

Class: Alkylating Agent (Nitrosourea). Cycle-nonspecific
Use: Brain tumors, multiple myeloma, melanoma
Kinetics: Excellent CNS penetration
S/E: N/V, delayed Myelosuppression

Question 8

What are common properties of Antimetabolite Antineoplastics?

Answer 8

• Structural analogs of compounds required in metabolism
• Falsely substitute in place of natural compound
• Most effective in tumors with rapid cell proliferation, thus:
• S PHASE SPECIFIC

Question 9

Methotrexate (MTX)

Answer 9

Class: Antimetabolite
Action: Binds dihydrofolate reductase (DHFR), blocking FH2 + dTMP –> FH4. CA cells also polymerize MTX to MTX-polyglutamate (a MORE potent DHFR inhibitor) more than normal cells
Use: ALL, choriocarcinoma, others
S/E: RENAL TUBULAR NECROSIS, N/V, intestinal epithelia damage, marrow suppression
Interactions: Displaces other drugs from serum albumin

Question 10

Leucovorin

Answer 10

AKA folinic acid - fully reduced folate (does not need DHFR). Normal cells can internalize Leucovorin more than CA cells, so is used to rescue host cells following MTX inhibition of DHFR.

Question 11

5-Fluorouracil (5-FU)

Answer 11

Class: Antimetabolite
Action: Pyrimidine analog. Activated to FUTP (inhibits RNA synth) and FdUMP (inhibits thymidylate synth and therefore DNA synth)
Use: Broad spectrum, esp colon, breast, basal cell carcinoma
S/E: N/V, Anorexia, Diarrhea, Myelosuppression

Question 12

Cytarabine (Ara-C)

Answer 12

Class: Antimetabolite
Action: Cytidine analog. Competes for phosphorylation with cytidine. Causes chain termination when integrated into DNA.
Use: Acute leukemias, ESPECIALLY AML. Lymphomas, head, neck
Kinetics: Given 2x/day for ~5 days - long infusion increases probability of killing CA cells not initially in S-phase. Afterwards, rapidly cleared.
S/E: DOSE-LIMITING myelosuppression, NEUROTOXICITY

Question 13

6-Mercaptopurine (6-MP)

Answer 13

Class: Antimetabolite
Action: Purine analog. Activated in cells, inhibits RNA & DNA synth.
Use: ACUTE LEUKEMIAS, chronic granulocytic leukemia
Kinetics: Metabolized by TPMT. Special considerations for pts with dysfunctional TPMT.
S/E: gradual marrow suppression, N/V, anorexia, JAUNDICE

Question 14

Thiopurine Methyltransferase

Answer 14

AKA TPMT. Important in 6-MP administration. Pts w/ 1 copy of nonfunctional TPMT - markedly reduced dose. Pts w/ 2 copies of nonfunctional TPMT CANNOT TOLERATE 6-MP. Too much 6-MP = serious marrow toxicity

Question 15

Hydroxyura

Answer 15

Class: Antimetabolite
Action: Inhibits RIBONUCLEOTIDE REDUCTASE (blocks ribonucleotides –> dNTPs), inhibiting DNA synth. Arrests cells at G1-S interface!
Note: Often used w/ radiation, as cells need dNTPs to repair radiation DNA damage.
Use: GRANULOCYTIC LEUKEMIA, head, neck
S/E: Marrow suppression, GI effects

Question 16

Vinblastine & Vincristine: Similarities

Answer 16

Class: Natural Products (Vinca Alkaloids)
Action: Bind tubulin, inhibiting microtubule and mitotic spindle formation. M-phase specific.

Question 17

Vinblastine & Vincristine: Differences

Answer 17

USES. VINB: lymphonas, breast. VINC: ALL, lymphomas, Wilm’s tumor, neuroblastoma, others
MARROW SUPPRESSION: VINB: Dose-limiting suppression! VINC: Much less marrow toxicity.
OTHER S/E: VINB: epithelial ulcerations. VINC: Alopecia, peripheral neuropathy (neuromuscular effects)

Question 18

Taxanes (incl. Paclitaxel)

Answer 18

Class: Natural Products
Action: Binds tubulin beta-subunit, STABILIZING microtubules. Binding site DIFFERENT than vinca alkaloids. Blocks at G2/M interface.
Use: Refractory ovarian CA, breast.
Use with: Cisplatin and/or radiation (RADIOSENSITIZER)
S/E: Dose-limiting leukopenia, periph. neuropathy, myalgia/arthalgia

Question 19

Doxorubicin

Answer 19

Class: Natural Products. Cycle-specific phase-nonspecific
Action: 1) Intercalates in DNA, distorts helix. 2) Causes lipid peroxidation, generation of ROS. 3) Binds DNA + TopoII (prevents strand break repair). Some anti-angiogenic properties.
Use: Wide spectrum, among most active drugs. Lymphomas, breast, ovary, SMALL CELL LUNG, many others.
S/E: CARDIOMYOPATHY (prevent w/ dexrazoxane - chelates Fe, prevents ROS damage), marrow suppression, alopecia, GI effects

Question 20

Bleomycin

Answer 20

Class: Natural Products
Action: Fe-containing glycopeptides that bind DNA; causes single- & double-strand breaks. G2/M-phase specific
Use: Broad spectrum. GERM CELL TUMORS of TESTES/OVARIES, head, neck, lung, lymphomas, others
S/E: Little marrow suppression. PULMONARY TOXICITY, SKIN VESICULATION, HYPERPIGMENTATION (lung & skin have low levels of inactivating enzyme), FEVER (50%)
Note: IRON IS CRITICAL. OTHER METALS DO NOT WORK.

Question 21

Etoposide (VP16)

Answer 21

Class: Natural Products
Action: Irreversibly stabilizes DNA-topoisomerase II complexes –> IRREPARABLE dsDNA breaks. Blocks at G2/M interface.
Use: Broad. Lymphomas, acute leukemia, small cell lung, testis
S/E: Dose-limiting leukopenia, alopecia, GI effects

Question 22

Filgrastim (G-CSF)

Answer 22

AKA: Granulocyte colony stimulating factor
Class: Natural Product (BRM)
Action: Promotes neutrophil expansion
Use: Recover pt from chemo-induced neutropenia / marrow suppression
S/E: BONE PAIN (33%)

Question 23

Trastuzumab

Answer 23

Class: “Natural Product”
Action: Humanized mAb; binds HER2 receptor (human epidermal growth factor), blocking cell proliferation
Use: Metastatic breast CA that overexpresses HER2 (25-30%); HER2+ gastroesophageal CA
Use with: Paclitaxel
S/E: Cardiomyopathy, hypersensitivity, infusion rxns

Question 24

Cisplatin

Answer 24

Class: Misc. (Platinum coordination complex). Cycle-specific phase-nonspecific
Action: Activated by hydrolysis; causes DNA crosslinks. Also inhibits thioredoxin reductase (TrxR), and directly promotes apoptosis.
Use: Broad. TESTICULAR, ovarian, head, neck, bladder, sm. cell lung, colon, esophagus, etc.
Use with: etoposide, bleomycin - TESTICULAR CANCER!
Use with: paclitaxel - ovarian cancer
S/E: NEPHROTOXICITY, OTOTOXICITY, periph. neuropathy, ELECTROLYTE DISTURBANCES, 100% N/V, marrow suppression

Question 25

Oxaliplatin, Carboplatin

Answer 25

Similar to cisplatin.
S/E: Less nephrotoxicity and some other effects, BUT:
Use: Less broad than cisplatin. HOWEVER:
Oxaliplatin is best platinum agent for colorectal CA (e.g. in FOLFOX)