Efficacy testing of WR-2721 in Great Britain or everything is black and white at the gray lab

Abstract

In this issue of the journal, Stewart et ~1.‘~ report their studies on the ability of WR-2721 (S-2-(3-aminopropylamino)ethylphosphorothioic acid) to protect three different murine tumors from ionizing radiation. Most investigators in this area are familiar with the conclusions reached, since they have been presented at four national and international meetings over the past few years,4,5*‘2,‘3 but only in summary form. With publication of the present data, it is now possible to examine the validity of these conclusions, which bear heavily on the proposed use of this type of drug in combination with radiation theraPY. Two major conclusions are reached by these investigators. The first is that “similar protection factors can be achieved in experimental tumors and in normal mouse skin for equal administered doses of WR-2721 and for the same interval between injection and irradiation.” In fact, these investigators have pointed out repeatedly that WR2721 can increase the radiation resistance of one of their tumors by a factor of 2.8,4,5.‘2.‘3,‘5 but the maximum protection they observe in the skin amounts to a 1.6-fold increase.14 Second, and perhaps even more surprising, they compare their skin data with published reports on tumor protection and suggest a “remarkable similarity” to their own data. This latter conclusion was of particular interest, since a number of investigators, including ourselves, had thought they had seen more protection in the skin than in the tumor.2~8~9~“~‘7~‘8~23~24 Although the data are presented in derived form, it is possible to examine them more closely than has been possible in the past, and in doing so we have not come to the same conclusions. Consider first Stewart et ~1’s’~ argument that published reports on tumor protection are consistent with their conclusion of equal protection of skin and solid tumors. This argument is summarized in Figure 5b of their report, and, we must agree that, as plotted, there is little evidence of greater protection of skin than of tumors. The point is, however, that the plot is an invalid one for at least three reasons: inclusion of inappropriate data, inaccurate plotting of other data, and the irrelevance of the comparison itself. First, two of the data points, including the remarkable tumor protection at the top of the plot (Figure 5b) are for leukemias, and these types of tumors have never been a part of the proposal for use of WR-2721 in radiation therapy. At the outset,23 we assumed that the differential protection we were observing was the product of deficient vascularity and/or blood flow, so there was no logical basis for including them in the proposal. Harris and Phillips6 demonstrated protection of the P388 ascitic leukemia by WR-2721 soon thereafter, which only reinforced the exclusion of leukemias from the proposed application. Our present understanding of the problem suggests that leukemias will be well protected by WR2721 for a number of reasons: ascitic tumors will have ready access to intraperitoneally injected WR-2721; in the early stages of growth, such as is the case here, the leukemias are well-oxygenated and this tends to optimize protective drug effectiveness? leukemias apparently lack the membrane restriction to the absorption of WR-2721, which is found in most solid tumors;2’ and ascitic fluid can convert WR-2721 into a radioprotector which is readily absorbed by normal and tumor tissues alike.*’ Since we know that WR-2721 does protect ascitic leukemias and why it does so, inclusion of them in any plot which purports to evaluate the efficacy of WR-2721 in radiation therapy is misleading. Even when we exclude these data points for the leukemias from Figure 5b,” the remaining plot does not provide strong evidence for greater protection of the skin than of the tumors. This raises the second problem with this comparison: some of the data have been plotted incorrectly. Lowy and Baker’ reported that WR-2721 increased the resistance of the KHT sarcoma by a factor of 1.2, not 1.4 as plotted in Figure 5b. In our initial studies on a mammary carcinoma,23 we reported a tumor protection factor of 1.14 (cure) or 1. I5 (time to produce takes), not a factor of 1.3 as plotted in Figure 5b. Last, in our studies on a murine lung adenoma,” we observed no