Anti Cancer drugs continued with Pyrimidine Analogs

Question 1

Next and the last group of Anti-metabolites are the Pyrimidine Analogs. First category were the Fluoropyrimidines. And first drug was 5-Fluorouracil, what are the pharmacokinetics?

Answer 1

PK:

• -administered IV and given topically for skin cancer
• -good penetration into CSF
• -mainly catabolized by the enzyme dihydropyrimidine dehydrogenase (DPD). A partial or complete deficiency of the DPD enzyme results in severe toxicity

Question 2

What is the MOA for 5-Fluorouracil (Anti-metabolite fluoropyrimidine)

Answer 2

5-Fluorouracil (5-FU) is converted to:

• -5-Fluoro-2-deoxyuridine-5-monophosphate (Fdump) which forms a ternary complex with the enzyme thymidylate synthase (TS) and the reduced folate (N5,N10 methylene tetrahydrofolate)– results in inhibiton of DNA synthesis through thymineless death. Increasing levels of N5,N10 methylene THF potentiates the activity of 5-FU
• -5-Fluorouridine-5-Triphosphate (FUTP) which is then incorporates into RNA, where it interferes with RNA processing and mRNA translation
• -5-Fluorodeoxyuridine-5-Triphosphate (FdUTP) which can be incorporated into cellular DNA, resulting in inhibition of DNA synthesis and function.

Question 3

What are the clinical applications and AE of 5-Fluorouracil?

Answer 3

First line drug against colorectal cancer
Activity Against: solid tumors like: breast, stomach, pancreas, esophagus, liver, head and neck and anus
AE:
–myelosuppression, GI toxicity, skin toxicity manifested as hand foot syndrome and neurotoxicity

Question 4

The other Pyrimidine Analog within the Anti-metabolites category is Capecitabine, what are the pharmacokinetics?

Answer 4

Orally available prodrug of 5-FU
Activated by a three step enzymatic conversion to 5-FU. First two steps occur in the liver while the last step occurs in the tumor and it is catalyzed by the enzyme thymidine phosphorylase
Expression of thymidine phosphorylase has been shown to be significantly higher in a broad range of solid tumors than in corresponding normal tissue, particularly breast and colorectal cancer.

Question 5

What are the clinical applications and adverse effects of Capecitabine?

Answer 5

Clinical:
–first line treatment of metastatic colorectal cancer
–metastatic breast cancer
Adverse:
–diarrhea, hand-foot syndrome, myelosuppression and mucositis but their incidence is significantly less than that observed with intravenous 5-FU.

Question 6

The next category under the Pyrimidine Analogs for the Anti-metabolites are the Deoxycytidine Analogs. First drug in the category is Cytarabine (ara-C), what are the pharmacokinetics?

Answer 6

PK:

• -IV
• -not effective orally due to deactivation by deamination in the intestinal mucosa
• -does not enter CNS
• -metabolized through extensive oxidative deamination to ara-U
• -both ara-C and ara-U are excreted by kidney

Question 7

What is the MOA for Cytarabine (ara-C)?

Answer 7

S phase specific antimetabolite
Converted to cytosine arabinoside Triphosphate which then:
–competitively inhibits DNA polymerase alpha (blockade of DNA synthesis)
–competitively inhibits DNA polymerase beta (blockage of DNA repair)
–incorporated into RNA and DNA. leads to interference with chain elongation and defective ligation of fragments of newly synthesized DNA.

Question 8

What are the clinical applications and adverse effects of cytarabine?

Answer 8

Activity is limited exclusively to hematologic malignancies, including acute myelogenous leukemia and non-hodgkin’s lymphoma
Not active against solid tumors
AE:
–myelosuppression, n/v, mucositis and neurotoxicity

Question 9

The other anti-metabolite Deoxycytidine Analog is Gemcitabine. What are the Pharmacokinetics and MOA?

Answer 9

PK:
–IV infusion ; –deaminated to difluorodeoxyuridine and excreted in urine
MOA:
–phosphorylated to nucleoside di and triphosphate which inhibit DNA synthesis. This inhibition is the result of:
1. Inhibition of ribonucleotide reductase by Gemcitabine diphosphate, which reduces the level of deoxyribonucleoside triphosphates required for the synthesis of DNA
2. Incorportation of Gemcitabine triphosphate into DNA which results in chain termination

Question 10

What are the clinical applications and adverse effects of Gemcitabine?

Answer 10

Clinical: Broad Spectrum of Activity
—solid tumors (pancreatic, non small cell lung, bladder, ovarian, soft tissue and sarcoma)
–hematologic malignancies (non hodgkins lymphoma)
AE:
–myelosuppression, n/v, flu like syndrome and renal microangiopathy syndrome

Question 11

Next category of anti-cancer drugs are Microtubule Inhibitors. Microtubules are essential for formation of mitotic spindle. Mitotic Spindle is required during the process of cell division into two daughter cells. What are the classes of microtubule inhibitors?

Answer 11

1. Vinca Alkaloids:
   - -Vinblastine and Vincristine
2. Taxanes:
   - -Paclitaxel and Docetaxel

Question 12

First up for the Microtubule Inhibitors are the Vinca Alkaloids. What are the MOA for these drugs?

Answer 12

Binds to B-tubulin on a portion of the molecule that overlaps with the GTP binding domain. The ability of the b-tubulin to polymerize with alpha tubulin into microtubules is inhibited. This disrupts assembly of microtubules, which are an important part of the cytoskeleton and the mitotic spindle.
–this inhibitors effects result in mitotic arrest in metaphase, bringing cell division to a halt, which then leads to cell death by apoptosis

Question 13

Vinblastine is first Vinca Alkaloid drug, what are the clinical applications and AE?

Answer 13

CLinical:
–Hodgkins and Non-Hodgkin’s Lymphoma, breast cancer, and germ cell cancer
AE:
–n/v, bone marrow suppression, Alopecia

Question 14

Vincristine is the 2nd Vinca Alkaloid drug, what are the clinical applications and AE?

Answer 14

Clinical:
–Hematological malignancies: ALL, Hodgkins and Non Hodgkins Lymphoma
–Pedatric Tumors: Rhabdomyosarcoma, neuroblastoma and Wilms Tumor
AE:
–neurotoxicity with peripheral neuropathy, paralytic ileus, myelosuppression, alopecia, optic atrophy, SIADH

Question 15

Next drug for the Microtubule Inhibitors are the Taxanes. What are the Pharmacokinetics?

Answer 15

PK:
–Metabolized by liver P450 system and nearly 80% of these drugs is excreted in feces via hepatobiliary route. Dose reduction is required in patients with liver dysfunction

Question 16

What is the MOA for Taxanes?

Answer 16

Bind to the beta-tubulin subunit of microtubules at the site distinct from the Vinca Alkaloid Binding site
Unlike the Vinca Alkaloids, taxanes promote microtubule polymerization and inhibit depolymerization.
–stabilization of the microtubule in a polymerized state arrests cells in mitosis and eventually leads to the activation of apoptosis.

Question 17

First drug in the Taxanes category is Paclitaxel, what are the clinical applications and AE?

Answer 17

Clinical:
—solid tumors: ovarian, advanced breast, NSCLC and small cell lung cancer, head and neck, esophageal, prostate, and bladder cancer and AIDs related Kaposi’s Sarcoma
AE:
—N,V, hypotension, arrhythmias, neruotoxicity, myelosuppression and hypersensitivity reactions

Question 18

Abraxane (Albumin-bound Paclitaxel formulation) is approved for use in metastatic breast cancer. In contrast to Paclitaxel, this formulation has the following properties:

Answer 18

Not associated with HSR and pre-mediation to prevent such reactions is not required
Associated with reduced myelosuppressive effects compared to paclitaxel
Neurotoxicity that results appears to be more readily reversible than is typically observed with paclitaxel

Question 19

The second Taxane is Docetaxel, what are the clinical application and AE?

Answer 19

Clinical:
–2nd line therapy in advanced breast cancer and NSCLC
–major activity in head and neck cancer, small cell lung cancer, gastric cancer, advanced platinum-refractory ovarian cancer and bladder cancer
AE:
–Hypersensitivity, neurotoxicity (does not cause neuropathy as frequently as Paclitaxel)
–Fluid retention (pre treat with dexamethosone)
–Myelosuppression and Neutropenia:
–associated with Docetaxel is profound

Question 20

The next set of Drugs are the Epipodophyllotoxins. This class includes: Etoposide and Teniposide. What are the PK and MOA of this class of drugs?

Answer 20

IV and Etoposide can be given orally as well
Do not penetrate the BBB
Excreted in urine
MOA:
–Inhibits Topoisomerase II, resulting in DNA damage through strand breakage. Blocks cell in late S-G2 phase

Question 21

What are the clinical applications and AE of Epipodophyllotoxins (Etoposide and Teniposide)

Answer 21

Clinical:
—Etoposide is indicated for testicular cancer and small cell lung cancer
–Teniposide is indicated for refractory childhood acute lymphoblastic leukemia
AE:
–N/V, Alopecia and myelosuppression

Question 22

The next set of drugs are the Camptothecins ,this class includes: Topotecan and Irinotecan. What is the MOA of these drugs?

Answer 22

MOA:-
–inhibit activity of topoisomerase I, the key enzyme responsible for cutting and religating single DNA strands. Inhibition of this enzyme results in DNA damage

Question 23

Topotecan (which is a camptothecins), what are the PK, clinical applications and AE?

Answer 23

PK:
—main route of elimination is renal excretion and dosage must be adjusted in renal impairment
Clinical:
–second line therapy for advanced ovarian cancer following initial treatment with platinum based chemotherapy
–second line therapy for small cell lung cancer
AE:
–N/V and myelosupression

Question 24

Irinotecan (which is a camptothecins), what are the PK, clinical and AE?

Answer 24

PK:
–prodrug converted mainly in the liver to SN-38 metabolite, which is 1000x more potent as an inhibitor of topoisomerase I than the parent compound.
Clinical:
–metastatic colorectal cancer (Combined with 5-FU and Leucovorin)
AE:
–Diarrhea: early form (occurs within 24 hours after administration – tx with atropine) and late form (occurs 2-10 days after tx)

Question 25

Next set of drugs are the Anti-tumor Antibiotics. This class includes: Bleomycin and Anthracyclines (doxorubicin and danunorubicin). First lets start with Bleomycin what are the PK and MOA?

Answer 25

PK:
–SQ, IV, or IM
–Renal excretion so dose modification
MOA:
–cell cycle specific drug that causes accumulation of cells in the G2 phase of the cell cycle
–small peptide that contains a DNA binding region and an iron binding domain
–binds to DNA, which results in single and double strand breaks following free radical formation, and inhibition of DNA biosynthesis

Question 26

What are the AE and Clinical Applications of Bleomycin?

Answer 26

AE:
Pulmonary Fibrosis
Minimal bone marrow suppression 
Clinical:
Hodgkin's and Non-Hodgkin's Lymphoma
Germ Cell tumor, head and neck cancer and squamous cell cancer of the skin, cervix and vulva

Question 27

Next drug in the Anti-tumor Antibiotics are the Anthracyclines, what are the PK and MOA?

Answer 27

PK:
–IV and dose reduction for liver dysfunction
MOA:
–inhibition of topoisomerase II
–high affinity binding to DNA through intercalation with blockage of the synthesis of DNA and RNA, and DNA strand scission
–generation of semiquinone free radicals and oxygen free radicals through iron dependent, enzyme mediated reductive process
–binding to cellular membrane to alter fluidity and ion transport.

Question 28

What are the adverse effects of Anthracyclines?

Answer 28

1. Myelosupression (dose limiting toxicity) (neutropenia)
2. Mucositis
3. Erythema and desquamation of the skin observed at sites of prior radiation therapy called radiation recall reaction
4. Cardiotoxicity: Acute (first 2-3 days and presents with arrhythmias, transient) or Chronic (dose dependent, dilated cardiomyopathy associated heart failure resulting from increased free radicals within the myocardium)
   - -tx with Dexrazoxane prevents or reduces anthracycline induced cardiotoxicity

Question 29

First Anthracycline is Doxorubicin. What are some features?

Answer 29

Clinical activity:

• -breast, endometrium, ovary, testicle, thyroid, stomach, bladder, liver, and lung
• -childhood cancers: neuroblastoma, ewings sarcoma, osteosarcoma, and rhabdomyosarcoma
• -hematologic malignancies: ALL, multiple myeloma, and Hodgkins/Non-Hodgkins Lymphoma
• -combination regiments so generally used in combo with other anti cancer agents

Question 30

The other Anthracycline is Daunorubicin, what are some features?

Answer 30

Tx of acute myeloid leukemia

Limited efficacy against solid tumors