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Prodrug could help curb skin toxicity related to EGFR-inhibiting cancer drugs
September 02, 2009(PHILADELPHIA) There may be a way around the harsh skin toxicity associated with a widely used cancer drug, according to a study published online this week in Cancer Biology and Therapy by researchers from City of Hope and the Kimmel Cancer at Jefferson.
Cetuximab (Erbitux) is a monoclonal antibody that binds to and inhibits the epidermal growth factor receptor (EGFR). It is widely used to treat colorectal cancer and head and neck cancer. Although cetuximab and other EGFR inhibitors are associated with a lower rate of side effects compared with conventional chemotherapy, adverse effects of the drugs often include a dose-limiting skin rash and gastrointestinal symptoms.
Adverse events in antibody therapy are frequently due to the binding of antibodies to normal tissue in addition to tumor tissue, according to Ulrich Rodeck, M.D., Ph.D., professor of Dermatology and Cutaneous Biology at Jefferson Medical College of Thomas Jefferson University. By "masking" the antibodies so they preferentially bind to the tumor tissue, the toxicity may be reduced or avoided.
"We've designed a prodrug in which the antibody is masked by an engineered form of the antigen, preventing it from binding to antigen on normal tissue," Dr. Rodeck said. "However, when the antibody reaches the tumor tissue, enzymes prevalent at tumor sites cleave the mask off, and the antibody can now engage the antigen at the tumor site."
The prodrug contains the antigen binding sites of two different EGFR-specific antibodies: 425 (matuzumab) and C225 (cetuximab). Each antibody is connected via peptide linker to the antigen recognized by the opposite antibody. The linkers contain sites susceptible to proteolytic cleavage by metalloprotease 9 (MMP-9), an enzyme that is frequently overexpressed in epithelial malignancies. Cleavage of the complex leads the antibodies to become "unmasked" and able to bind to the antigens on the tumor cells.
"This work provides proof-of-principle evidence that the concept is feasible, and sets the stage for future studies using tumors grown in vivo," Dr. Rodeck said.
Thomas Jefferson University
"We've designed a prodrug in which the antibody is masked by an engineered form of the antigen, preventing it from binding to antigen on normal tissue," Dr. Rodeck said. "However, when the antibody reaches the tumor tissue, enzymes prevalent at tumor sites cleave the mask off, and the antibody can now engage the antigen at the tumor site."
The prodrug contains the antigen binding sites of two different EGFR-specific antibodies: 425 (matuzumab) and C225 (cetuximab). Each antibody is connected via peptide linker to the antigen recognized by the opposite antibody. The linkers contain sites susceptible to proteolytic cleavage by metalloprotease 9 (MMP-9), an enzyme that is frequently overexpressed in epithelial malignancies. Cleavage of the complex leads the antibodies to become "unmasked" and able to bind to the antigens on the tumor cells.
"This work provides proof-of-principle evidence that the concept is feasible, and sets the stage for future studies using tumors grown in vivo," Dr. Rodeck said.
Thomas Jefferson University
Cancer Drugs Current Events and Cancer Drugs News RSSNew imagining technique could lead to better antibiotics and cancer drugs
A recently devised method of imaging the chemical communication and warfare between microorganisms could lead to new antibiotics, antifungal, antiviral and anti-cancer drugs, said a Texas AgriLife Research scientist.
Taking aim at mysterious DNA structures in the battle against cancer
Designers of anti-cancer drugs are aiming their arrows at mysterious chunks of the genetic material DNA that may play a key role in preventing the growth and spread of cancer cells, according to an article in the current issue of Chemical & Engineering News, ACS' weekly newsmagazine.
Duke develops nano-scale drug delivery for chemotherapy
Going smaller could bring better results, especially when it comes to cancer-fighting drugs.
Next-generation microcapsules deliver 'chemicals on demand'
Scientists in California are reporting development of a new generation of the microcapsules used in carbon-free copy paper, in which capsules burst and release ink with pressure from a pen.
Sensor biochips could aid in cancer diagnosis and treatment
It is very difficult to predict whether a cancer drug will help an individual patient: only around one third of drugs will work directly in a given patient.
Melanoma treatment options 1 step closer
A targeted chemotherapy for the treatment of skin cancer is one step closer, after a team of University of Alberta researchers successfully synthesized a natural substance that shows exceptional potential to specifically treat this often fatal disease.
Experts issue call to reconsider screening for breast cancer and prostate cancer
Twenty years of screening for breast and prostate cancer - the most diagnosed cancer for women and men - have not brought the anticipated decline in deaths from these diseases, argue experts from the University of California, San Francisco and the University of Texas Health Science Center at San Antonio in an opinion piece published in the "Journal of the American Medical Association."
Metals could forge new cancer drug
Drugs made using unusual metals could form an effective treatment against colon and ovarian cancer, including cancerous cells that have developed immunity to other drugs, according to research at the University of Warwick and the University of Leeds.
Studying cancer in pet dogs to find new treatments for human patients
A team of scientists at the National Cancer Institute (NCI) in Bethesda, USA, says that studying pet dogs with cancer could yield valuable information on how to diagnose and treat human cancers.
KEAP1 Keeps major cancer-promoting protein at bay
A tumor-suppressing protein snatches up an important cancer-promoting enzyme and tags it with molecules that condemn it to destruction, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center reports this week in the journal Molecular Cell.
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