Recognition of tumor blood vessel normalization as a new antiangiogenic concept

To the editor:

We found the first evidence of drug-induced normalization of tumor blood vessels in 1970¹, and described it more definitively in 1972 (ref. 2). This was a new type of drug action. The drug we used was razoxane (ICRF 159; NSC 129943); by normalizing the characteristically chaotic tumor vasculature, it prevented tumor hemorrhages, blood-borne tumor-cell dissemination and metastasis³.

It was clear from the outset that the concept of normalization of pathologic vasculatures, which sustain and extend diseases such as cancer, arthritis, diabetic retinopathy and others, could have widespread application. It was also obvious that normalization of blood vessels could improve the availability of drugs and oxygen to disease areas, and thus improve combination therapy². Razoxane was therefore investigated in clinical trials, both as a single antiangiogenic and antimetastatic agent and in combination with cytotoxic drugs or radiotherapy. It proved to be highly effective in psoriasis^3,4, psoriatic arthropathy⁵, Kaposi sarcoma⁶ and Crohn disease⁷. It significantly delayed recurrences of Duke grade C colorectal cancer⁹, and it potentiated radiotherapy¹⁰ and some cytotoxic drugs¹¹. All these results have been published in a series of papers, reviews^12,13 and abstracts.

It was surprising, therefore, that in an entirely hypothetical commentary by R.K. Jain¹⁴ proposing normalization of tumor vasculature as a new rationale for antiangiogenic therapy, none of the papers in the fairly extensive literature on razoxane were thought to be relevant to the claims put forward in this article, as none were quoted. The justification for these omissions from the scientific record seems to be that the article was specifically about the possible potentiation of cytotoxic drugs or radiotherapy if they were combined with antiangiogenic agents such as TNP-470, STI-571, C225 or Herceptin—all of which (except TNP-470) are said to have shown vascular normalization, though this is not evident from the publications cited¹⁴. The evidence for vascular normalization by Herceptin comes from a brief report from Jain's laboratory¹⁵.

Extensive clinical trials have examined the combination of Herceptin with cytotoxic drugs. In breast cancer, the combination of Herceptin and doxorubicin increases severe cardiotoxicity sixfold, and that of Herceptin and paclitaxel by fourfold (http://www.herceptin.com/herceptin/physician/pi.htm), with only a marginal increase in survival. In contrast, the D-isomer of razoxane (dexrazoxane; approved by the US Food and Drug Administration) was highly effective in reducing severe doxorubicin cardiotoxicity, and nearly doubled median survival time in very similar clinical trials¹⁶.

Our original results showing razoxane normalization of tumor blood vessels have recently been fully confirmed by the National Cancer Institute in an extensive in vitro and in vivo investigation¹⁷. This shows that razoxane-induced changes in the tumor vasculature can provide the morphologic basis for improved delivery of therapeutics and for prevention of circulating tumor-cell escape.

See Reply to 'Recognition of tumor blood vessel normalization as a new antiangiogenic concept' by Jain.