Enantioselective Organocatalytic Conjugate Addition of α ...
Conjugate drug shows antileukemic activity
1
Bifunctional agent links antibody to genistein H N °* B43— N— C— (CH 2 )c— N - f ^-N—Ο—ιί^Γ Μ I M° H H l Υ | ^ Monoclonal Cross-linking agent I 1 antibody Genistein Conjugate drug shows antileukemic activity A conjugate drug that combines a monoclonal antibody with an enzyme inhibitor is effective in animal tests against the predominant form of acute lymphoblastic leukemia (ALL), the most common type of childhood cancer and the second most common type of acute leukemia in adults. In experiments with mice, Fatih M. Uckun of the biotherapy program at the University of Minnesota, Minneap- olis, and coworkers used a monoclonal antibody to selectively deliver an en- zyme inhibitor to human B-cell precur- sor (BCP) cells, the type of cell that be- comes cancerous in ALL [Science, 267, 886 (1995)]. Less than one-tenth the maximum tolerated dose of the conjugate drug killed more than 99.999% of human BCP leukemia cells with which the mice had been inoculated. The conju- gate showed higher activity than cur- rently available ALL medicines (such as vincristine, methylprednisone, and L-asparaginase) or radiation treatment in comparative tests in mice. According to Uckun and coworkers, the conjugate's "favorable pharmacody- namic features, superior cytotoxic activi- ty against leukemia cells resistant to ra- diation as well as to several other estab- lished antileukemia agents, and lack of systemic toxicity recommend the clinical evaluation of this ... protein tyrosine kinase inhibitor in BCP leukemia pa- tients who have failed standard thera- py/ 7 However, many drugs fail to live up to their initial promise when they enter human clinical trials. Protein tyrosine kinases play a key role in initiating the uncontrolled cell growth of leukemia. But it is difficult to inhibit the enzymes because they are inside BCP cells, where drugs can't eas- ily penetrate. Uckun and coworkers solved this problem by taking a soybean-based natural product called genistein, which is a protein tyrosine kinase inhibitor, and conjugating it to B43, a monoclonal antibody that binds to CD19 receptors on BCP cell surfaces. CD19 receptors are physically and functionally associated with the intra- cellular protein tyrosine kinases. Bind- ing of the B43-genistein conjugate thus brings genistein close to the protein ty- rosine kinases, resulting in inhibition of the enzymes. This interferes with criti- cal intracellular signaling pathways and causes the BCP cells to die by apo- ptosis (programmed cell death). B43-PAP—a conjugate of B43 and a protein synthesis inhibitor called poke- weed antiviral protein—is a similar anti- leukemic drug developed earlier by Uckun and coworkers. In Phase I and II clinical trials to study safety and efficacy, B43-PAP "has induced complete remis- sions in patients who failed convention- al therapy, including very aggressive regimens like bone marrow transplanta- tion," says Uckun. This result shows that B43 "can indeed target leukemia cells successfully and bring a toxic substance to the cells," he says. The antileukemic activity of B43- genistein was significantly higher than, that of B43-PAP in the mouse tests. However, Uckun says it would be pre- Researchers at the University of Texas at Austin have discovered that a widely used class of drugs forms a previously unknown type of complex with DNA. The findings may have implications for the rational design of new antibacterial and anticancer drugs with higher poten- cy and fewer side effects than existing drugs of the same class. The new type of complex forms be- tween DNA and a class of quinolone and quinobenzoxazine drugs of great therapeutic importance. The quinolones include commercial antibacterial agents In quinobenzoxazine-DNA complexes, one drug molecule (yellow) intercalates into DNA (purple), a second (green) binds to the DNA surface, and the two drug molecules are bound together as a dimer by two Mg 2 * ions (gray spheres). As shown here, a second quinobenzoxazine dimer may also bind to an adjacent site on DNA. Phosphate groups on DNA that coordinate with the drug are shown in blue. mature to speculate on how B43- genistein will fare in human clinical tri- als. In fact, he says ALL patients differ so much "that it would be too optimis- tic to think that any single agent will be successful." Currently, 10 or more drugs are used in combination to treat ALL, and the remission and cure rate from therapy with those drugs is quite high, espe- cially for children. B43-genistein shows much higher antileukemic activity than those agents in the mouse studies, but "that doesn't mean it's going to replace them," says Uckun. "The idea would be to use it to kill those cells that escape conventional ther- apy so that you amplify your treatment alternatives," he says. "The combination of this new agent with conventional drugs may overcome the resistance of cancer cells and may improve treatment outcomes." Stu Borman Drugs form new type of complex with DNA FEBRUARY 20, 1995 C&EN 33
Transcript of Conjugate drug shows antileukemic activity
Bifunctional agent links antibody to genistein
H N ° * B43— N— C— (CH2)c— N - f ^ - N — Ο — ι ί ^ Γ Μ
I M° H Hl Υ | ^ Monoclonal Cross-linking agent I 1
antibody Genistein
Conjugate drug shows antileukemic activity A conjugate drug that combines a monoclonal antibody with an enzyme inhibitor is effective in animal tests against the predominant form of acute lymphoblastic leukemia (ALL), the most common type of childhood cancer and the second most common type of acute leukemia in adults.
In experiments with mice, Fatih M. Uckun of the biotherapy program at the University of Minnesota, Minneapolis, and coworkers used a monoclonal antibody to selectively deliver an enzyme inhibitor to human B-cell precursor (BCP) cells, the type of cell that becomes cancerous in ALL [Science, 267, 886 (1995)].
Less than one-tenth the maximum tolerated dose of the conjugate drug killed more than 99.999% of human BCP leukemia cells with which the mice had been inoculated. The conjugate showed higher activity than currently available ALL medicines (such as vincristine, methylprednisone, and L-asparaginase) or radiation treatment in comparative tests in mice.
According to Uckun and coworkers, the conjugate's "favorable pharmacodynamic features, superior cytotoxic activity against leukemia cells resistant to radiation as well as to several other established antileukemia agents, and lack of systemic toxicity recommend the clinical evaluation of this . . . protein tyrosine kinase inhibitor in BCP leukemia patients who have failed standard therapy/7 However, many drugs fail to live up to their initial promise when they enter human clinical trials.
Protein tyrosine kinases play a key role in initiating the uncontrolled cell growth of leukemia. But it is difficult to inhibit the enzymes because they are inside BCP cells, where drugs can't easily penetrate.
Uckun and coworkers solved this problem by taking a soybean-based natural product called genistein, which is a protein tyrosine kinase inhibitor, and conjugating it to B43, a monoclonal antibody that binds to CD19 receptors on BCP cell surfaces.
CD19 receptors are physically and functionally associated with the intracellular protein tyrosine kinases. Binding of the B43-genistein conjugate thus
brings genistein close to the protein tyrosine kinases, resulting in inhibition of the enzymes. This interferes with critical intracellular signaling pathways and causes the BCP cells to die by apo-ptosis (programmed cell death).
B43-PAP—a conjugate of B43 and a protein synthesis inhibitor called poke-weed antiviral protein—is a similar antileukemic drug developed earlier by Uckun and coworkers. In Phase I and II clinical trials to study safety and efficacy, B43-PAP "has induced complete remissions in patients who failed conventional therapy, including very aggressive regimens like bone marrow transplantation," says Uckun. This result shows that B43 "can indeed target leukemia cells successfully and bring a toxic substance to the cells," he says.
The antileukemic activity of B43-genistein was significantly higher than, that of B43-PAP in the mouse tests. However, Uckun says it would be pre-
Researchers at the University of Texas at Austin have discovered that a widely used class of drugs forms a previously unknown type of complex with DNA. The findings may have implications for the rational design of new antibacterial and anticancer drugs with higher potency and fewer side effects than existing drugs of the same class.
The new type of complex forms between DNA and a class of quinolone and quinobenzoxazine drugs of great therapeutic importance. The quinolones include commercial antibacterial agents
In quinobenzoxazine-DNA complexes, one drug molecule (yellow) intercalates into
DNA (purple), a second (green) binds to the DNA surface, and the two drug molecules
are bound together as a dimer by two Mg2* ions (gray spheres). As shown here, a
second quinobenzoxazine dimer may also bind to an adjacent site on DNA.
Phosphate groups on DNA that coordinate with the drug are shown in blue.
mature to speculate on how B43-genistein will fare in human clinical trials. In fact, he says ALL patients differ so much "that it would be too optimistic to think that any single agent will be successful."
Currently, 10 or more drugs are used in combination to treat ALL, and the remission and cure rate from therapy with those drugs is quite high, especially for children. B43-genistein shows much higher antileukemic activity than those agents in the mouse studies, but "that doesn't mean it's going to replace them," says Uckun.
"The idea would be to use it to kill those cells that escape conventional therapy so that you amplify your treatment alternatives," he says. "The combination of this new agent with conventional drugs may overcome the resistance of cancer cells and may improve treatment outcomes."
Stu Borman
Drugs form new type of complex with DNA
FEBRUARY 20, 1995 C&EN 33
