Research Commentary: Anti-Angiogenic Drugs
The Ribbon

The news: A front-page article in the New York Times on May 3, 1998 reported that angiostatin and endostatin, two substances produced by a tumor itself, can cause tumors in mice to shrink when given at artificially high concentrations.

Is this research new? No! There were no new findings that were reported to the media on May 3rd. Two papers in leading scientific journals Cell and Nature had reported on the anti-tumor effect of angiostatin and endostatin in mice in 1997 (O¹Reilly et al., 1997; Boehm et al., 1997). The motivation behind the recent media focus was not clear, since no new research announcements had been made to the press.

What is angiogenesis? A small tumor is a cluster of abnormally replicating cells, and can survive using the normal blood supply of its host organ. However, for a tumor to grow and progress further, it needs blood to reach the rapidly dividing cells deep within it. To meet this need, the tumor stimulates the growth of new blood vessels‹a process called angiogenesis. Simultaneously, many tumors produce inhibitors of angiogenesis, such as angiostatin and endostatin, to inhibit the growth of blood vessels. Researchers believe that by producing a balance of stimulators and inhibitors, tumors regulate the growth of new blood vessels, and prevent the overgrowth of blood vessels.

The research behind the news: Two scientific papers published in 1997 described how anti-angiogenic drugs act. In the first paper, O¹Reilly et al. (1997) used recombinant DNA technology to put the mouse endostatin gene into bacteria, and produce larger quantities of endostatin in bacteria. This mouse endostatin was harvested and injected into mice. All the mice tested had been treated with tumor causing agents and had tumors of a specific size already. Ten milligrams of endostatin, for every kilogram of body weight of mouse, was found to inhibit tumor growth and even reduce the size of existing tumors. The treatment was effective against many different tumors tested in mice ‹ of skin, lung, blood and fibrous tissue. No side effects were noticeable in the endostatin treated mice. The tumors did not grow for as long as the endostatin injections were continued.

Besides being very effective, anti-angiogenic drugs were found to have an additional advantage over conventional chemotherapy. Many tumors can initially be controlled with the chemotherapeutic drugs to which they respond. However, tumor cells change and adapt very fast. Most failures of cancer treatment occur when the tumor cells acquire resistance for the chemotherapeutic drugs that were keeping them in check. Anti-angiogenic treatments target stable normal cells and not the fickle tumor cells. Hence, the frequency of acquiring tolerance to this treatment is expected to be low. In the second paper, Boehm et al. (1997) demonstrated that even after many repeated treatments with endostatin, tumors continued to shrink and did not acquire resistance or tolerance for this particular therapy.

Recent unpublished reports at scientific meetings indicate that a combination of angiostatin and endostatin is more effective against tumor growth. A new study published in Nature (July 17, 1998), reports that the combined use of radiation and angiostatin is more effective in mice than either therapy alone. There are also many reports of other anti-angiogenic drugs being evaluated against tumors.

Related research: Related research indicates that recombinant human angiostatin (rather than the mouse version) is also effective in inhibiting tumors in mice (Lannutti et al., 1997; Sim et al., 1997). It is also encouraging to note that the endostatin protein produced by mice is very similar in composition to that produced in humans (Saarela et al., 1998; Standker et al., 1997). However, all the trials so far have been in one experimental model (mice) and it is too early to predict if the anti-tumor effects would also occur in humans. It would be useful to know if the human angiostatin works similarly against tumors in other mammals such as rats or rabbits. The big question, to which no one yet has any answer, is if the human body can tolerate such artificially high levels of these inhibitors.

What is the forecast for this therapy? The first step, on which scientists are already working, is the large-scale production of the human and mouse versions of these drugs. When this step is successful, the drugs will have to be critically analyzed for toxic impurities. Only then can a human clinical trial begin. The National Cancer Institute predicts that even if all goes smoothly, it will be at least a year before clinical trials are possible. We are at least three to five years away from the time when these drugs would be available for cancer patients.

Written by Renu Gandhi, BCERF Research Associate

References

Boehm, T. et al. (1997). Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390, 404-407.
Lannutti, B.J. et al. (1997). Human angiostatin inhibits murine hemangioendothelioma tumor growth in vivo. Cancer Research 57, 5277-5280.
Mauceri, H.J. et al. (1998). Combined effects of angiostatin and ionizing radiation in antitumour therapy. Nature 394, 287-291.
O¹Reilly, M.S. et al. (1997). Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277-285.
Saarela, J. et al. (1998). Complete primary structure of two variant forms of human type XVIII collagen and tissue-specific differences in the expression of the corresponding transcripts. Matrix Biology 16, 319-328.
Sim, B.K.L. et al. (1997). A recombinant human angiostatin protein inhibits experimental primary and metastatic cancer. Cancer Research 57, 1329-1334.
Standker, L. et al. (1997). Isolation and characterization of the circulating form of human endostatin. FEBS Letters 420, 129-133.

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Research Commentary: Anti-Angiogenic Drugs The Ribbon

Research Commentary: Anti-Angiogenic Drugs
The Ribbon