Biomedical Engineering Reference
In-Depth Information
Table 17.2 Mechanisms of Test Compounds
Compound
Mechanism of action
5-Fluorouracil
Potent antitumor agent
Inhibits aminoisobutyrate-pyruvate aminotransferase
Induces apoptosis in human primary and metastatic colon
adenocarcinoma in vitro
Arrests cell cycle at G2
Oxaliplatin
Antitumor platinum compound with activity against colorectal cancer;
cytotoxicity follows formation of DNA adducts
Induces apoptosis
Camptothecin
Binds irreversibly to the DNA topoisomerase I complex, blocking the
cell cycle in S phase
Induces apoptosis in many normal and cancer cell lines
Leucovorin
The active form of the B complex vitamin, folate, used in combination
with chemotherapy to maintain folate levels
Protects normal cells and increases antitumor effects of 5-FU
zebrafish. These drugs have been shown to induce apoptosis in human colon cancer
cells. 5-FU, a potent antitumor agent that inhibits aminoisobutyrate-pyruvate ami-
notransferase, has been used as a chemotherapeutic for more than 40 years and it
remains the most widely prescribed colon cancer drug. This drug also induces
apoptosis in human primary and metastatic colon adenocarcinoma cell lines and
arrests the cell cycle at G2. Oxaliplatin is a platinum compound that was approved by
the FDA for colon cancer treatment in 2002. The mechanism of this drug involves
formation of DNA adducts, which causes cytotoxicity and induces apoptosis.
Camptothecin binds irreversibly to the DNA topoisomerase I complex, blocking the
cell cycle in the S phase and inducing apoptosis. Although leucovorin, the active form
of the B complex vitamin, folate, is not a cancer drug, it protects normal cells and
enhances 5-FU efficacy. If drugs induced similar effects on Xt colon cancer cells, we
expected decreased number of colon cancer cells or decreased antigen expression,
both resulting in lower chemiluminescence signal. Three concentrations of each drug,
determined by LC 10 experiments, were assessed as described below. Drug treatment
began immediately after cell transplant and Xt zebrafish were incubated in drug
solution at 35 C continuously for 3 days. At 3 days post treatment (dpt), Xt zebrafish
were then processed for ELISA experiments.
17.4.5 Effect ofCancerDrugsonHumanColonCancer
Cells in Xt Zebrafish
We first estimated LC 10 of each cancer drug by treating nontransplanted, 3dpf
zebrafish with test drugs for 3 days (see Section 17.3). LC 10 for camptothecin was
0.24
m
M; however, since no lethality was observed at the highest test concentration,
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