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Endostatin Promising Treatments For AIDS-related Cancer

August 13, 2003
Ohio State University
New research suggests that the anti-tumor compound endostatin delivers a one-two punch to Kaposi's sarcoma – the most common AIDS-related cancer.

COLUMBUS, Ohio – New research suggests that the anti-tumor compound endostatin delivers a one-two punch to Kaposi's sarcoma – the most common AIDS-related cancer.

Endostatin seems to strike Kaposi's sarcoma (KS) lesions by preventing existing tumors from growing new blood vessels and also by stopping KS tumor cells from migrating through the body, said Susan Mallery, the study's lead author and a professor in the department of oral and maxillofacial surgery and pathology at Ohio State University's College of Dentistry.

A hallmark of the advanced stages of AIDS in many cases, KS lesions often appear as purplish growths on the palate and at various places on the skin. Mallery and her colleagues treated KS cells – taken from malignant lesions on AIDS patients – with endostatin.

Kaposi's sarcoma is similar to most other cancers in that it relies on the growth and formation of blood vessels in order to thrive. But KS is unique in that its cells both produce and respond to substances called growth factors – something not seen in most other types of cancer. This ability gives KS tumors an extra advantage in establishing new tumors throughout the body.

"It also makes KS an incredibly aggressive disease," Mallery said. But treating KS cells with endostatin in the laboratory seemed to stop the cells in their tracks – the cells had lost their ability to migrate and invade in response to growth factors.

While the laboratory results of the current study are promising, endostatin has proved a challenge in treatment.

"Human clinical trials in which endostatin was administered intravenously haven't been highly successful, but subsequent studies on animals where the subjects were treated with steady, local levels of endostatin have shown promise," she said. "A controlled, sustained and local release of endostatin might be a good approach when treating human patients with KS."

The study appears in a recent issue of the Journal of Cellular Biochemistry.

The researchers isolated KS cells from biopsy-confirmed tumors on AIDS patients and treated the cells with endostatin. Patients providing the cells had either failed medication therapy or hadn't received treatment. Groups of cells were treated with endostatin for specific lengths of time, ranging from 5 to 150 minutes – treating cells in such a fashion gave researchers an idea of how long it would take for endostatin to affect the cells.

Within a half an hour, endostatin had noticeably altered the shape of the KS cells – the cells had flattened out and had lost their characteristic spindle form. Previous studies have shown that endostatin quickly binds to and inhibits the filaments that are necessary for cell movement.

After an hour and a half, endostatin had infiltrated the cells' nuclei, where it altered the process of transcription – a mechanism by which a cell's genetic material reproduces. After nearly two hours, endostatin had cleared out of the cells, supporting the idea that a continuous, controlled-release of endostatin in the tumor area is a viable treatment option, Mallery said.

"KS cells are phagocytic – they eat things," she said. "Therefore, endostatin uptake by KS cells is rapid, after which the KS cells fail to mobilize the filaments needed for movement. If we could stop this KS cell migration in a human patient, then we could prevent a tumor from progressing beyond a small lesion."

Homosexual and bisexual men run the greatest risk for developing KS -- women rarely develop the disease.

In AIDS patients, KS is caused by human herpesvirus-8 (HHV-8), a sexually transmitted virus and one of the few established cancer-causing viruses. HHV-8 infects B-cells, immune system cells that produce inflammation-causing cytokines. This production of cytokines triggers an increased production of primitive cells called endothelial progenitor cells – cells that help repair damaged blood vessels. But in the case of HIV-positive people, this rampant production of endothelial cells can give rise to KS tumors.

Mallery believes that endostatin may stop these endothelial progenitor cells from proliferating. Endostatin is a potent angiostatic drug – in addition to preventing blood vessels from forming, it also stops new tumors from developing. In the case of KS, endostatin appears to cut the communication between the tumor cells and two key growth factors – VEGF and bFGF – both important to the formation of new blood vessels and in the development of new tumors.

It's thought that these growth factors help KS cells invade different parts of the body – that's why lesions can show up in random places.

"That makes a tremendous amount of sense in Kaposi's sarcoma, because the disease typically appears as numerous lesions on the body," Mallery said. "That's unusual for most cancers, which generally start with an isolated tumor and then spread."

Kaposi's sarcoma is far less common today than it was in the 1980s and the early 1990s. Back then, it was an early sign of full-blown AIDS infection. Subsequent developments of effective anti-HIV treatments, such as the potent highly active anti-retroviral therapy (HAART), significantly decreased the number of AIDS patients that developed KS.

"We're not seeing nearly the amount of KS that we saw a decade or more ago – it's become more of an end-stage disease," Mallery said. "The people developing KS now are typically those who have failed HAART."

Mallery said the next step is to look into using biodegradable polymer particles to provide a controlled, sustained release of endostatin over the span of several months.

"Endostatin is a good drug, but the problem is that treating a patient intravenously with endostatin won't yield a therapeutic concentration at the tumor site," she said.

"Treating KS lesions locally could be particularly helpful for patients in whom the disease is limited to the skin and mucus membranes," Mallery continued. "Based on what we saw in the laboratory, the cells wouldn't be able to make another tumor after treatment with endostatin, and the existing tumor would likely regress."

Support for this research came from the National Institutes of Health/National Institute of Dental and Craniofacial Research and the National Cancer Institute.

Mallery conducted the study with David Schuller, Director of the James Cancer Hospital and Solove Research Institute at Ohio State; Ralph Wilson, Ping Pei, Gregory Ness, Jennifer Bradburn and Robert Renner, all with the departments of oral maxillofacial surgery and pathology and periodontoloty at Ohio State's College of Dentistry; Mark Morse, with Ohio State's School of Public Health and Ohio State's Comprehensive Cancer Center; and Fredika Robertson, of the department of molecular virology, immunology and medical genetics at Ohio State.

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Materials provided by Ohio State University. Note: Content may be edited for style and length.

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Ohio State University. "Endostatin Promising Treatments For AIDS-related Cancer." ScienceDaily. ScienceDaily, 13 August 2003. <>.
Ohio State University. (2003, August 13). Endostatin Promising Treatments For AIDS-related Cancer. ScienceDaily. Retrieved June 12, 2024 from
Ohio State University. "Endostatin Promising Treatments For AIDS-related Cancer." ScienceDaily. (accessed June 12, 2024).

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