Research in the 1970s revealed that angiogenesis—the growth of new blood vessels—is an essential component of tumor growth and metastasis. J. Folkman, a leading investigator who laid the groundwork in this area, hypothesized that new blood vessels at the tumor site were necessary for expansion of the tumor spheroid beyond 1-2 mm, the rate limiting diameter beyond which the diffusion of nutrients and waste products could no longer support tumor growth.
  This discovery led to an explosion of research toward the development of antiangiogenic compounds, both natural and synthetic. Some of the many angiogenesis inhibitors under intense investigation today include proteolytic peptides (e.g. angiotensin, endostatin), metalloproteinase and plasminogen activator inhibitors, immune mediators, chemokines, extracellular matrix molecules and oligosaccharides.
  In 1983, Lee and Langer published a study showing that “shark cartilage contains a substance that strongly inhibits the growth of new blood vessels toward solid tumors, thereby restricting tumor growth”, opening the possibility that compounds derived from shark cartilage could be used in the development of antiangiogenic drugs.

Now, a liquid extract of shark cartilage—AE-941—has made it through Phase I and II clinical trials with encouraging evidence supporting its clinical efficacy and tolerability.
  In a open label, multicentre study presented here by Dr. Jean Latreille, Head of the Medical Oncology Department at Montreal’s Hôtel-Dieu Hospital, AE-941 was given for

12 weeks to patients with refractory lung cancer. The study was expanded in Phase II with 19 additional patients at the dose level selected on the basis of Phase I safety and preliminary efficacy results. If patients derived benefit from treatment, they were continued on the drug in an open-ended extension of the study. Doses given (in mL/day) were 30 (n=6), 60 (n=13), 120 (n=13), and 240 (n=48). The primary objectives of the trial were to establish the safety and toxicity profile of AE-941, identify signs of efficacy on the main clinical indicators, and determine the optimal dose for Phase III studies. Endpoints included safety assessment (adverse events reported), pain (analgesics consumed), status of performance (ECOG score), body weight, tumor assessment, and quality of life evaluation (EORTC score).
  No serious adverse event (AE) related to AE-941 was seen and only 7% of non-serious AEs were related to the agent; none of these led to withdrawal in the study. There was a positive trend in favor of a dose-response effect with regards to analgesic consumption, weight loss, and stabilization of tumor progression. The number of patients showing stabilization of tumor progression was 38% higher in the group of patients treated with the highest dose (240 mL/day) compared to those having receiving the lowest dose (30 mL/day). For the total group of patients, the estimated median survival time was more than 25 weeks.
  Based partly on these and encouraging results from earlier trials, the U.S. National Cancer Institute has approved a large, randomized, multicentre, double-blind, placebo-controlled Phase III study of AE-941 for the treatment of lung cancer to begin in May, 1999. U.S. Food & Drug Administration approval

is expected to follow soon. The trial is expected to enroll several hundred cancer patients and to last several years.
  In an interview, Dr. Gerald Batist, Director of the McGill Centre for Translational Research in Cancer, Jewish General Hospital, Montreal, and a coauthor of the study, stressed that AE-941 is a unique drug that is going through a legitimate drug development program, unlike most of the other shark cartilage products on the market.
  “AE-941 is a liquid cartilage extract prepared by a proprietary extraction technique, Dr. Batist noted. “It has demonstrated activity in all the classical angiogenesis in vitro models and it also has a metalloproteinase inhibition activity which is important. There’s no question in anybody’s mind that this is a true drug development—that there is real activity. In animals, it makes tumors shrink.”

The first rigorous study of shark cartilage powder (SCP) and cancer, involving 60 patients and conducted under the auspices of the Cancer Treatment Research Foundation, found that the substance was ineffective for advanced cancer (Miller et al, J Clin Oncol 1998;16:3649-3655). Patients who had been previously treated and who had advanced cancer and were given a commercially available SCP product at a dose of 1 g/kg tid for six weeks. At that time, those deemed fit to continue the study were treated for another additional six weeks.
At study end, there were no complete or partial responses to SCP and the 16.7% rate of stable disease in patients taking it was similar to results in patients with advanced cancer treated with supportive care only. The authors also stated, “under the specific conditions of this study, shark cartilage as a single agent was inactive in patients with advanced-stage cancer and had no salutary effect on quality of life.”

In addition to its applications in oncology, AE-941 is under active research for use in the treatment of psoriasis, age-related macular degeneration, and veterinary osteoarthritis.

  In a study presented the 5th European Congress on Psoriasis, September 1999, interim results of a Phase I/II clinical trial of AE-941 for psoriasis indicated there were no adverse side effects at all dosage levels during the first three months of the trial. Some patients had significant improvement in their condition, measured by the Psoriasis Area and Severity Index (PASI) index. Out of the 30 evaluable patients, three out of eight treated at the highest dose experienced at least a 30% improvement in total PASI score, with the maxium improvement being 67%. Final results of the trial will be presented at the 57th Annual Meeting of the American Academy of Dermatology in New Orleans, March 19-24, 1999.
  Commenting on how an angiogenesis inhibitor might work against psoriasis, Dr. Daniel Sauder, Head of the Department of Dermatology, Faculty of Medicine at the University of Toronto and lead author of the study, said, “We have done some basic studies to determine the mechanism of action of AE-941 and, in addition to its antiangiogenic activity, it has an anti-inflammatory effect on certain components of the immune system. It is able to modify proinflammatory molecules and stimulate antiinflammatory molecules so that probably has a role in its effect on psoriasis.”
  In addition, Dr. Sauder remarked, one of the early signs of psoriasis is dilated vasculature in the upper layers of the skin: “It’s thought that this is involved in the pathogenesis of psoriasis and that these dilated vessels contribute to the release of inflammatory cells into the skin. So, by decreasing the vascularity, AE-941 could have a direct effect on the blood vessels in psoriatic lesions. It’s probably both mechanisms— antiiflammation and antiangiogenesis—that are causing beneficial effects in psoriasis.”
  Dr. Sauder also indicated that the antiangiogenesis effects of AE-941 are likely at the basis for it’s effect on macular degeneration, a condition marked by vascular overproliferation.
  Phase II results of AE-941 as monotherapy for prostate and breast cancer are expected later this year as well are Phase I results for its use in combination therapy in solid tumor cancers.