AIDS Treatment News No. 195 - March 18, 1994
Michael Marco
Angiogenesis -- the formation of new blood vessels -- takes place normally during wound healing. But abnormal angiogenesis is an important contributor to certain diseases. In cancer, for example, solid tumors must be able to stimulate the growth of new blood vessels to nourish the tumor cells, or they cannot grow beyond a small size. And evidence now suggests that Kaposi's sarcoma may not be a true cancer in most cases, but instead may be due to abnormal blood-vessel growth caused by dysregulation of angiogenesis.
Since normal growth of blood vessels is not necessary at most times during a person's life, researchers are developing drugs which inhibit angiogenesis (both normal and abnormal), in the hope of creating an entirely new class of treatments for cancer and for KS. This article outlines the current status of the research into three of these potential drugs, and describes the clinical trials which are currently open. (Note: For previous coverage of angiogenesis inhibitors, see AIDS TREATMENT NEWS issues #188, #162, #135, and #122.)
Three anti-angiogenesis compounds currently in early clinical trials as KS treatments are Tecogalan (SP-PG, also called DS- 4152), TNP 470 (formerly called AGM-1470), and recombinant human platelet factor 4 (rPF4). They have only been tested in a small number of patients with KS, and have mostly shown a lessening of KS-associated swelling, and some minor activity on existing lesions. Many researchers now feel that angiogenesis inhibitors might be most effective in preventing new lesions from occurring rather than affecting pre-existing lesions.(1) If this is true, these drugs might work best as maintenance therapy after systemic chemotherapy. Tecogalan (SP-PG): Los Angeles, New York, San Antonio, San Francisco
Tecogalan is an angiogenesis inhibitor which has been isolated from the bacterium Arthrobacter. Tecogalan prevents a protein (called fibroblast growth factor) from binding to endothelial cells (the cells which line the insides of blood vessels) and stimulating those cells to migrate and reproduce. In animal tests conducted by Robert Gallo, M.D., and colleagues, "nude" mice (special immunodeficient mice) were given a form of KS by injection of human KS cells; Tecogalan "led to degeneration of newly formed vascular lesions."(2)
Four sites are currently recruiting patients for a phase I dose-escalating pharmacokinetic and safety trial of intravenous Tecogalan. Preliminary results have shown some activity on existing lesions, and a considerable lessening of edema (swelling). So far, no serious toxicities have been seen, except for prolonged APTT (activated partial thromboplastin time, which can affect the time it takes for blood to clot), which normalizes after the infusion.(3) Some patients have also noted chills and fever.
Volunteers may have any T-helper count for this trial, but they must have at least five cutaneous (skin) lesions, and no evidence of systemic visceral involvement. During the first dose, volunteers will be hospitalized for 24 hours for monitoring; later doses will be given on an outpatient basis.
This trial is being conducted at the following four sites:
* Los Angeles: Kenneth Norris Jr. Cancer Hospital/USC. Investigator: Parkash Gill, M.D. Contact: 213/224-6668.
* New York City: Memorial Sloan-Kettering Cancer Center. Investigator: Susan Krown, M.D. Contact: 212/639-7426.
* San Antonio: Cancer Therapy Research Center. Investigator: Gail Eckardt, M.D. Contact: 210/616-5798.
* San Francisco: San Francisco General Hospital. Investigator: James Kahn, M.D. Contact: 415/476-9296x84104 TNP-470: Bethesda, Boston, Chicago, Los Angeles, St. Louis
TNP-470 is a synthetic chemical analog of fumagillin, which is produced by a fungus. In 1990, researchers at Harvard Medical School found that fumagillin and TNP-470 inhibited angiogenesis in laboratory tests, and inhibited the growth of solid tumors in mice; TNP-470 was found to be less toxic and 50 times as powerful as fumagillin.(4) Researchers at the U.S. National Cancer Institute also found that TNP-470 inhibited abnormal spindle cells, which have a major role in the development of KS.
Animal tests showed that very large doses, given all at once, caused toxicity, most notably small hemorrhages in the brain, lungs, heart, and retinas of dogs. The drug was better tolerated when given as an infusion. Therefore, initial clinical testing used a one-hour infusion, starting at low doses.
In preliminary results from the phase I trial of TNP-470 in persons with KS, researchers at the NCI reported that the drug showed some activity on existing lesions (especially in lessening edema, or swelling), and a decrease in the development of new lesions. No dose-limiting toxicities were found.(5)
This trial, as well as a four-site study by the AIDS Clinical Trials Group (ACTG), is still ongoing; both are open for volunteers. There is no T-helper count requirement for these dose-escalating trials, but patients with pulmonary KS are excluded from the NCI trial; the ACTG trial excludes all potential volunteers with symptomatic visceral KS.
Note that the NCI trial, although conducted in Bethesda, Maryland (near Washington, D.C.), is open to volunteers from throughout the country. The NCI will pay travel expenses (except for the first trip), and will pay a stipend toward living expenses while volunteers are in Bethesda. The trial lasts 24 weeks.
The first listing, below, is for the NCI trial. The other four are locations of sites for the ACTG trial.
* Bethesda, Maryland: U.S. National Cancer Institute. Investigator: Robert Yarchoan, M.D. Contact: 301/496-8959.
* Boston: Beth Israel Hospital. Investigator: Bruce Dezube, M.D. Contact: Beryl Chapman, 617/735-4149.
* Chicago: Northwestern University Medical Center. Investigator: Jamie Von Roenn, M.D. Contact: 312/908-9412.
* Los Angeles: Kenneth Norris Cancer Center Hospital/USC. Investigator: Parkash Gill, M.D. Contact: 213/224-6668.
* St. Louis: Washington University School of Medicine. Investigator: Lee Ratner, M.D. Contact: Mary Gould, R.N., 314/454-0058.
Recombinant Platelet Factor 4 (rPF4): Los Angeles, Philadelphia, San Francisco
Recombinant platelet factor 4, a genetically engineered version of a substance normally found in the body, has been found to inhibit endothelial cells in laboratory tests.(6) Another research group, following up this result, found that rPF4 also inhibited KS cells in a dose-dependent manner.(7)
In the early phase I/II (safety and preliminary efficacy) trial, rPF4 was injected into one lesion, while another lesion on the same patient was given an inactive injection as a control. An anti-KS effect was found in six of the 12 patients given rPF4. The only side effect was a mild rash around the lesion in approximately 20 percent of the patients.(8)
There are three phase I/II trials of rPF4 which are currently open for volunteers in the U.S. They differ in how the drug is administered; subcutaneously in Los Angeles, intralesionally in Philadelphia, and intravenously in San Francisco. There is no requirement for T-helper count. These trials will last for a maximum of eight weeks.
* Los Angeles: Kenneth Norris Cancer Center/USC. Investigator: Parkash Gill, M.D. Contact: 213/224-6668.
* Philadelphia: Graduate Hospital of Philadelphia. Investigator: Arthur Staddon, M.D. Contact: 215/893-7520.
* San Francisco: San Francisco General Hospital. Investigator: James Kahn, M.D. Contact: 415/476-9296 x84104.
References
1. Pluda JM, Parkinson DR, Feigal E, and Yarchoan R. Noncytotoxic approaches to the treatment of HIV-associated Kaposi's sarcoma. ONCOLOGY. December 1993; volume 7, number 12, pages 25-33.
2. Nakamura S, Sakurada S, Salahuddin SZ, and others. Inhibition of development of Kaposi's sarcoma-related lesions by a bacterial cell wall complex. SCIENCE. 1992; volume 255, pages 1437-1440.
3. Gill PS, PA-C Kidane S, Tulpule A, and others. A phase 1 study of DS-4152, a novel angiogenesis inhibitor in the treatment of AIDS-related Kaposi's sarcoma. E.O.R.T.C., Amsterdam, March 15-18, 1994.
4. Ingber D, Fujita T, Kishimoto S, and others. Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumor growth. NATURE. December 6, 1990; volume 348, pages 555-557.
5. Pluda JM, Wyvill K, Lietzau J, and others. A phase I trial of TNP-470 (AGM-1470) administered to patients with HIV- associated Kaposi's sarcoma (KS). The First National Conference on Human Retroviruses and Related Infections, Washington, D.C., December 1993 [abstract #31].
6. Maione TE, Gray GS, Petro J, and others. Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides. SCIENCE. January 5, 1990; volume 247, pages 77-79.
7. Miles S, Rezai A, Martinez-Maza O, and Maione TE. Recombinant platelet factor 4 (rPF4) and a non-heparin binding derivative inhibit AIDS-Kaposi sarcoma derived cell lines. VII International Conference on AIDS, Florence, June 1991 [abstract # W.A.1066].
8. Kahn J, Ruiz R, Kerschmann R, and others. A phase I/II study of recombinant platelet factor 4 (rPF4) in patients with AIDS-related Kaposi's sarcoma (KS). Proceedings: Annual Meeting of the American Society of Clinical ONCOLOGY. 1993; volume 12:A4.
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