Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
[CANCER RESEARCH56. 2677—2678, June 1, 1996] Letters to the Editor Correspondence re: J. A. Knol et aL, Incorporation of 5-Bromo-2'-deoxyuridine into Colorectal Liver Metastases and Liver in Patients Receiving a 7-Day Hepatic Arterial Infusion. Cancer Res., 55: 3687—3691,1995 The report by Knol et a!. (1) on BrdUrd' incorporation into hepatic metastases is an excellent clinical extension of their earlier work with animal models (2). In addition to its direct practical application to radiosensitization, their findings confirm, for the biology of these specific tumors, the suitability of the 14-day infusions that are stand Timothy J. Kinsella University of Wisconsin Madison, Wisconsin 53792 References ard practice for fluorodeoxyuridine and that are also used for inves 1. Knol, J. A., Walker, S. C., Robertson, J. M., Yang, Z., DeRemer, S., Stetson, P. L., tigations of BrdUrd and IdUrd. The biological effects of IdUrd and BrdUrd are largely dependent upon the fraction of thymidine that is replaced in DNA. It has been difficult to determine whether one of these analogues has a therapeutic advantage compared with the other. In the second paragraph of the “Discussion,― Knol et al. compare their findings with BrdUrd with our results for IdUrd (3). We are concerned that readers will have the impression that BrdUrd is superior to IdUrd. if comparable conditions Ensminger, W. D., and Lawrence, T. S. Incorporation of 5-bromo-2'-deoxyuridine into colorectal liver metastases and liver in patients receiving a 7-day hepatic arterial infusion. Cancer Res., 55: 3687—3691,1995. 2. Lawrence, T. S., Davis, M. A., Maybaum, J., Mukhopadhyay, S. K., Stetson, P. L., Normolle, 0. P., McKeever, P. E., and Ensminger, W. D. The potential superiority of bromodeoxyuridine to iododeoxyuridine as a radiation sensitizer in the treatment of colorectal cancer. Cancer Res., 52: 3698—3704, 1992. 3. Speth, P. A., Kinsella, T. J., Chang, A. E., Klecker, R. W., Belanger, K., and Collins, J. M. Selective incorporation of iododeoxyuridine in DNA of hepatic metastases versus normal human liver. Clin. Pharmacol. Ther., 44: 369—375,1988. are used, the incorporation into tumor DNA for BrdUrd and IdUrd are essentially identical. After 7 days of hepatic arterial infusion, Knol et al. reported finding an average of 11.6% replacement of dThd by BrdUrd. As noted in the discussion, 3% replacement was found by our group for a 3-day IdUrd infusion (2). We would expect that incorporation into DNA would remain linear with time under these conditions; thus, our 3-day value of 3% would increase to 7% for a 7-day infusion. Although this projected value of 7% IdUrd is still lower than the 11.6% BrdUrd result from intrahepatic arterial delivery, there is a large difference in route of administration. Although Knol et a!. state that our IdUrd data were generated with arterial delivery, the 3% value actually corresponds to i.v. delivery. For IdUrd delivered by the arterial route, we reported that incorporation into tumor DNA in creased by about 70%, from 3 to 5.2%. Therefore, we expect the 7% value for a 7-day i.v. infusion to increase to 12% for the i.a. route. It would be a more elegant comparison if the same infusion length and route of delivery were utilized, but there is certainly no indication of increased BrdUrd incorporation under comparable conditions. Equal IdUrd and BrdUrd incorporation leads generally to similar biological effects. As noted in the second paragraph of the “Introduction― (1), “for the same extent of incorporation, IdUrd probably produces slightly greater radiosensitization than BrdUrd does.― Although there are many exciting new targets being discovered and developed for anticancer therapy, the proven human activity of halo genated pyrimidines as radiosensitizers, chemosensitizers, and direct cytotoxic agents merits further research toward optimization of their utility. Jerry M. Collins2 Raymond W. Klecker Clinical Pharmacology Research Food and Drug Administration 4 Research Court Rockville, Maryland 20857 Alfred E. Chang University of Michigan Ann Arbor, Michigan 48109 Received 11/8/95; accepted 3/28/96. I The abbreviations used are: BrdUrd, 5-bromo-2'-deoxyuridine; deoxyuridine. 2 To whom requests for reprints should Reply We thank Dr Collins et al. (1) for the interest that they have taken in our work (2). However, we cannot concur with an unqualified contention that “if comparable conditions are used, the incorporation into tumor DNA for BrdUrd' and IdUrd are essentially identical― (italics theirs). Collins et al. (1) showed that after a 3-day hepatic arterial IdUrd infusion in two patients, there was a 5.1% IdUrd incorporation into colorectal hepatic metastasis DNA (3). However, their assumption that incorporation of IdUrd into tumor DNA is linear over 7 days is unlikely to be valid. The nonlinearity of incorporation is supported by findings from both of our laboratories that incorporation of both IdUrd and BrdUrd into HT29 colorectal cells plateaus at 4 days (4) and that, in transplanted HT29 xenografts in athymic mice, DNA BrdUrd incorporation after 2 days retards subsequent BrdUrd incorporation (5, 6), and the same is likely to be true for IdUrd. Collins et al. (1) in their letter have extrapolated from a 5.1% IdUrd DNA incorporation after a 3-day infusion to a projected 12% for a 7-day infusion, but we contend that that extrapolation is not justifiable from available data. Of perhaps similar therapeutic importance to the measure of tumor DNA incorporation of BrdUrd or IdUrd is the proportion of cells within the tumor exhibiting incorporation of the halopynmidine. We reported BrdUrd labeling in 83% of tumor cells in high-density labeled portions of colorectal liver metastases, 80% of tumor cells in moderate-density labeled portions, and 58% of tumor cells in low density labeled portions (2). Collins et al. (1) found a mean of 36% of tumor cells labeled with IdUrd after a 3-day hepatic arterial infusion and 32% of tumor cells labeled after a 3-day i.v. infusion (3). As suming no increased cytotoxicity with IdUrd as compared to BrdUrd, a labeling index similar to that found by us for colorectal metastases would be expected with a 7-day infusion of IdUrd, an indicator of the proportion of tumor cells that had entered or passed through S-phase during the infusion. However, IdUrd exhibits greater cytotoxicity than does BrdUrd at equimolar exposures (7, 8). At the concentrations of IdUrd achievable Received 11/8/95; accepted 3/28/96. IdUrd, 5-iodo-2'- I The abbreviations used are: BrdUrd, 5-bromo-2'-deoxyuridine; IdUrd, deoxyuridine. be addressed. 2677 Downloaded from cancerres.aacrjournals.org on August 11, 2017. © 1996 American Association for Cancer Research. 5-iodo-2'- REPLY TO LETfER TO EDITOR with hepatic artery manifested and result labeling as compared Because there are infusion, this greater toxicity is likely to be in decreased DNA incorporation and tumor cell to an equimolar dose of BrdUrd. differences in the biological effects of BrdUrd References and IdUrd and because these effects are likely to be amplified with prolonged hepatic arterial infusions in vivo, we assert that the predic tion of Collins et a!. (1) of equivalent IdUrd incorporation and cell labeling in hepatic colorectal metastases after a ‘7-day hepatic artery infusion requires demonstration. James A. Knol Theodore S. Lawrence William D. Ensminger Philip L Stetson Suzette C. Walker Zizoamin Yang Susan DeRemer University of Michigan Ann Arbor, Michigan 48109 I. Collins. J. M., Kiecker, R. W., Chang, A. E., and Kinsella, T. J. Correspondence re: J. A. Knol et aL, Incorporation of 5-bromo-2'-deoxyuridine into colorectal liver metastases and liver in patients receiving a 7-day hepatic arterial infusion. Cancer Res., 55: 3687—3691,1995. Cancer Res., 56: 2677, 1996. 2. Knol, J. A., Walker, S. C., Robertson, J. M., Yang, Z., DeRemer. S., Stetson, P. L, Ensminger, W. A., and Lawrence, T. S. Incorporation of 5-bromo-2'-deoxyuridine intocolorectallivermetastasesandliverin patientsreceivinga ‘1-day hepaticarterial infusion. Cancer Res., 55: 3687—3691,1995. 3. Speth, P. A. J., Kinsdlla, T. J., Chang, A. E., Klecker, R. W., Belanger, K., and Collins, J. M. Selective incorporation of iododeoxyuridine into DNA of hepatic metastases versus normal human liver. Clin. PharmacoL Ther., 44: 369—375,1988. 4. Lawrence, T. S., Davis, M. A., Maybaum, J., Stetson, P. L, and Ensminger, W. D. The dependenceof halogenatedpyrinsidineincorporationand radiosensitization on the duration ofdrug exposure. list. J. Radiat. OncoL Biol. Phys., 18: 1393—1398,1990. 5. Lawrence, T. S., Davis, M. A., Stetson, P. L, Maybaum, J., and Ensininger, W. D. Kinetics of bromodeoxyuridine elimination from human colon cancer cells in vitro and in vivo. Cancer Res., 54: 2964—2968,1994. 6. Rodriguez, R., Riner, M. A., Fowler, J. F., Kinsella, T. J. Kinetics of cell labeling and thymidine replacement after continuous infusion of halogenated pyrimidines in vivo. hit. J. Radiat. OncoL Biol. Phys., 29: 105—1 13, 1994. 7. Djordjevic, B., Szybalski, W. Genetics of human cell lines. ifi. Incorporation of 5-bromo- and 5-iododeoxyuridlineinto the deoxyribonucleic acid of human cells and its effect on radiation sensitivity. J. Exp. Med., 112: 509—531, 1960. 8. Lawrence, T. S., Davis, M. A., Maybaum, J., Mukhopadhyay, S. K., Stetson, P. L, Normolle, D. P., McKeever, P. E., and Ensminger, W. D. The potential superiority of John M. Robertson William Beaumont Hospital Royal Oak@Michigan 48072 bromodeoxyuridine to iododeoxyuridine as a radiation sensitizer in the treatment of colorectal cancer. Cancer Res., 52: 3698—3704,1992. 2678 Downloaded from cancerres.aacrjournals.org on August 11, 2017. © 1996 American Association for Cancer Research. Correspondence re: J. A. Knol et al., Incorporation of 5-Bromo-2 ′-deoxyuridine into Colorectal Liver Metastases and Liver in Patients Receiving a 7-Day Hepatic Arterial Infusion. Cancer Res., 55: 3687−3691, 1995−−Reply James A. Knol, Theodore S. Lawrence, William D. Ensminger, et al. Cancer Res 1996;56:2677-2678. Updated version E-mail alerts Reprints and Subscriptions Permissions Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/56/11/2677.2.citation Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected]. Downloaded from cancerres.aacrjournals.org on August 11, 2017. © 1996 American Association for Cancer Research.