Download JA Knol et aL, Incorporation of 5-Bromo-2

[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.
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