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The interaction of radiation and cis-diamminedichloroplatinum (II) in intestinal crypt cells
0360-3016/79/081417-04$02.ooiO
fnt. J. Rocliafion Owo/oi~\’ Biol. f’hys.,, Vol. 5, pp. 1417-1420 Pergamon Press Ltd., 1979. Printed in the U.S.A.
??Cis-Platinum
THE INTERACTION DIAMMINEDICHLOROPLATINUM
OF RADIATION AND CIS(II) IN INTESTINAL CRYPT CELLS-t
H. LUK, M.D.,* GLENDA Y. Ross, B.S., THEODORE M.D.,and LAWRENCE S. GOLDSTEIN, Ph.D.
KENNETH
L. PHILLIPS,
of Radiation Oncology, University of California, San Francisco, CA 94143, and SThe Claire Zellerbach Saroni Tumor Institute, Mount Zion Hospital, San Francisco, CA 94115
Department
The effect of radiation and cis-platinum in combination was studied in the intestinal crypt cell survival system of the LAF,mouse. The drug LDn,Jso was 22 mg/kg and the maximum tolerated dose (MTD)(LD,,) was 13 mg/kg. That dose caused 80% cell kill when given either 3 hrs after or 2 hrs before a dose of 1100 rad. When the MTD was given from -48 to +48 hrs relative to a dose of 1110 rad, survival fluctuated with minima at - 12 hrs, 0 and + 12 hrs. A radiation survival curve determined 2 hrs after an MTD drug dose was parallel to the control, but shifted to lower doses due to cell kill. The extrapolated D, was 280 rad, but the split dose survival ratio was only 1.3 compared to a control value of 7 at the same survival level. A repeat experiment with B,AF, mice yielded a survival ratio of 3 vs 6 for controls. Cis-platinum may reduce repair of radiation injury, as well as kill intestinal crypt cells. Cis-platinum,
Intestinal crypt cells, Maximum tolerated dose.
INTRODUCTION
METHODS
AND MATERIALS
II (cisDDP) is an anti-tumor agent currently used in the treatments of testicular, ovarian, bladder, and head and neck carcinomas, as well as other miscellaneous tumors, such as neuroblastomas and colon cancers.2~*,1”~21 Cis-DDP is a complex inorganic compound with platinum in the center and 2 chlorine and 2 ammonia atoms in the cis position. Its mode of action seems to be the inhibition of DNA synthesis by cross-linking DNA molecules and blocking mitosis at G,.“,14 Its cytotoxicity has been proven in many in viva and in vitro systems.“~4~s~‘3~1fi~‘X The cancer chemotherapeutic agents which have been extensively studied for modification of radiation effects on tumors and normal tissues include actinomycin D, Adriamycin, 5-fluorouracil, BCNU, cyclophosphamide, and bleomycin.‘O Recently cisDDP has been found to not only add to radiation cell kill in tumors, but also to act as a hypoxic cell sensitizer.’ In this study, we evaluate the response of intestinal crypt cells to different doses of radiation and cis-DDP, as well as to evaluate the different time intervals of administration of these two modalities.
IO-12 weeks, were used. They were housed 4-6 per cage, and were given laboratory chow and water ad libitum. One split dose experiment was carried out with B,AF, mice of similar age and source. Solutions of cis-DDP were prepared in water to allow injection of volumes of 0.01 ml/gm of body weight. The maximum tolerated dose (MTD or LD 0.0,7 the LDJ,, and the LDJ,,) of the cis-DDP were found by administering drug doses yielding IO-90% survival varying from 1 to 100% in groups of 10-15 mice. A 137Cs irradiator delivered a dose rate of 235 rad/minute. The mice were irradiated whole body in rotating lucite cages placed parallel to the axis of the linear radiation source and perpendicular to the beam. No anesthesia was used. Single radiation doses of 800 to 1800 rad were given in 200 rad increments. This group of mice was compared with a similar group which also received cis-DDP at the MTD 2 hrs prior to irradiation. Two experiments with single or split (3 hrs) radiation doses were also carried out 2 hrs after cis-DDP administration in order to determine the survival ratio, the ratio of
iThis investigation was supported by National Cancer
Cis-DDP was supplied by the Drug Development Branch of the Division of Cancer Treatment, National Cancer Institute in the form of clinical ampules.
Cis-platinum,
cis-diamminedichloroplatinum
Institute Research Grants CA17227 and CA20529 JDr. Luk is the recipient of an American Cancer Clinical Junior Faculty Fellowship.
Male
Society
1417
LAF,
mice,
age
1418
Radiation Oncology 0 Biology 0 Physics
number of surviving crypt cells per circumference for 2 fractions divided by the number for one fraction. Control survival ratios for similar cell numbers were used. Cis-DDP was given at the MTD at intervals of 48, 36, 24, 18, 12, 6, 2, or 0 hrs prior to or after a single dose of radiation of 1110 rad. The drug was administered at the MTD, 3/4 MTD, 1/2 MTD, or ‘14 MTD 2 hrs prior to or 3 hrs after a single radiation dose of 1100 rad. Four to six mice per data point were sacrificed by cervical dislocation 32/3 days after irradiation. The jejunum was removed from the animals, fixed in Tellyesniczky’s fixative, and processed for paraffin sectioning. Five micron sections were prepared from each specimen, stained with hematoxylin, phloxine, and safran, and scored for the number of regenerating crypts per circumference. These numbers were converted to crypt cells per circumference by the technique of Withers and Elkind.20
RESULTS Drug LD,,, determinations at 5 days and 60 days were 36 and 22 mgikg, respectively. The MTD of 13 mgikg yields less than 1% death. Fig. 1 demonstrates the radiation dose response of mouse intestinal crypt cells with or without prior administration of the MTD of cis-DDP. There is marked enhancement of the radiation effect with the addition of the drug at all radiation dose levels, with a shift of the curve to the left side. There does not appear to have been a change in the slope of the curve, however. Extrapolation to obtain the D, yields a value of 280 rad, as compared to 400 rad for controls, when correction for 80% cell kill by drug alone is made. The enhancement effects of cis-DDP at 4 different drug dose levels are shown in Fig. 2. The MTD yields an 80 % cell kill. There is more destruction of the intestinal crypt cells at dose levels of )/4 MTD and I/Z MTD, than at the dose of l/4 MTD, where the response is similar to the radiation only control group. There does not appear to have been a significant difference whether drug is given 2 hrs prior to or 3 hrs after irradiation. The effects of MTD doses of cis-DDP spaced +48 hrs relative to a single dose of radiation (1110 rad) are shown in Fig. 3. There is a decrease in the intestinal crypt cell survival when radiation and cis-DDP are given simultaneously. The effects of cis-DDP on radiation do not seem to diminish when the drug is given more than 2 hrs before or after radiation. The dips in the surviving crypt counts at 12 and 36 hrs before and 12 and 48 hrs after radiation may be related to the partial synchrony caused by either agent. Split dose studies carried out in LAF, mice
August 1979, Volume 5, Number 8
1000
r 0
‘=7c8
V 13 mg/Kg
600
1200 DOSE,
1600
-
RAD
Fig. 1. Radiation survival curves for intestinal crypt cells exposed to 13Ts gamma rays alone (0) or 2 hrs following (V) 13 mgikg of cis-DDP. 200
IOC
5a
lo-3.25
6.50
9.75
13.00
DOSE, mg/Kg
Fig. 2. Drug survival curves for intestinal crypt cells with cis-DDP in increasing doses given 2 hrs before (0) or 3 hrs after (0) 1100 rad of 13Ts gamma rays.
yielded survival ratios of 7 for control animals (cell number for single exposure 12) and 1.3 for animals pretreated with 0.75 MTD of cis-DDP (cell number for single exposure 7). A second experiment with BBAF, mice yielded survival ratios of 6 for controls and 3 for cis-DDP (single dose cell number 15 and 8, respectively).
Interaction
CIS-PLATINUM,
1000
of radiation and cis-platinum 0 LUK et 01.
13 mg/Kg
I
r
TIME
OF DRUG
INJECTION.
HR
Fig. 3. Crypt cell survival (0) as a function of time between administration of cis-DDP (13 mgikg) and 137Cs gamma rays (1110 rad).
DISCUSSION Cis-DDP is a potent cytotoxic agent, notwithstanding the fact that it was discovered by serendipity.‘” Renal damage has been identified as the major toxic effect.s The gastrointestinal toxicity in man includes marked nausea and vomiting, not usually relieved by antiemetics. Taylor, Tew and Jones’* showed that in rats the rate of DNA synthesis in the intestine 26 hrs after treatment with 6 mg cis-DDP per kg body weight was reduced to one tenth or less of the control level. With these facts in mind, the combined effects of radiation and cis-DDP on the intestinal mucosa needs to be examined since this drug is receiving greater recognition. The rather low LD5,j5 (36 mg/kg) and the 80 % cell kill caused by the MTD added to 1110 rad indicates that cisDDP alone is quite cytotoxic to intestinal crypt cells.
1419
Schenken et al. I7 studied the combined effects of radiation and methotrexate, cyclophosphamide, Adriamycin, and BCNU on the jejunum in mice, and concluded that excessive gastrointestinal toxicity may result if aggressive chemotherapy is closely spaced with radiation exposure for the treatment of abdominal neoplasms. Phillips et al. ‘* studied the intestinal microcolony survival in LAF, mice using radiation and actinomycin D, Adriamycin, BCNU, bleomycin, or cyclophosphamide, and found dose effect factors (DEF) ranging from 3.3 for Adriamycin given 2 days before radiation to 0.93 for actinomycin D given 7 days after radiation. The authors recommended the use of mouse model systems to test any cancer chemotherapeutic agents to be used in combination with radiation in humans. Phillips and Fu” further discussed the problems of quanitification of combined radiation and chemotherapy effects on normal tissues. There is still very limited information in terms of clinical experiences and perhaps more data accumulated in experimental animals. A dose effect factor between 1.1 and 1.8 has been found for most of the chemotherapeutic agents studied. In this study the DEF for cis-DDP at MTD is 1.3 for jejunal crypt cells at 2 hrs prior to irradiation (Fig. 1). However, our time interval study shows that the DEF may be greater when cis-DDP is given simultaneously with radiation. This should caution the clinicians that a markedly reduced dose of radiation or cis-DDP may be necessary when normal intestines are included in the radiation portal. The data are inconclusive concerning the effect of cis-DDP on repair of radiation injury, although the D, is slightly reduced and the split dose studies showed a lower survival ratio when cis-DDP was used. Complete split dose studies are underway for a wide range of time intervals. Interference with repair could be important in terms of normal tissue damage.
REFERENCES Douple,
Richmond, R.C., Logan, M.E.: E.B., Therapeutic potentiation in a mouse mammary tumor and an intracerebral rat brain tumor by combined treatment with cis-dichlorodiammineplatinum (II) and radiation. J. Clin. Hemat. 0~01. 7: M-603, 1977. Einhom, L.H., Donohue, J.: Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Ann. Internal Med. 87: 293-298, 1977. Gale, G.R., Atkins, L.M., Meischen, S.J., Smith, J.B., Walker, Jr., E.M.: Chemotherapy of advanced L1210 leukemia with platinum compounds in combination with other antitumor agents. Cancer Treat. Rep. 61: 445-450, 1977.
4. Ghanta. V.K.. Jones. M.T., Woodard, P. A., Durant, Cis-dichlorodiammineplatJ.R., ‘Hiramoto, R.N.: inum(II) chemotheapy in experimental murine mYelOma MOPC 103E. Cancer Research 37: 771-774, 1977. Heinen, E., Bassleer, R.: Cytological and cytochemical analysis of the effects of cis-dichlorodiaminoplatinum (II) on chick fibroblasts cultivated in I’itro. Chemotherapy 22: 253-261, 1976. Heinen, E., Bassleer, R.: Mode of action of cisdichlorodiammineplatinum (II) on mouse ehrlich ascites tumor cells. Biochem. Pharmac. 25: 1871-1875, 1976. Higby, D.J., Wallace, H.J., Albert, D.J., et al.: Diaminodichloroplatinum: a phase I study showing responses in testicular and other tumors. Cancer 33:
1420
1219-1225, 8. Hill, J.M., studies of treatment
Radiation Oncology 0 Biology 0 Physics
1974. Loeb, E., MacLellan, platinum coordination of various malignant
A., et ul. : Clinical compounds in the diseases. Cancer
Chemotherapy Rep. 59: 647-659, 1975. 9. Madias, N.E., Harrington, J.T.: Platinum ity. Amer. J. Med. 65: 307-314, 1978.
nephrotoxic-
10. Phillips, T.L.: Chemical modification of radiation effects. Cancer 39: 987-999, 1977. 11. Phillips, T.L., Fu, K.K.: Quantification of combined radiation therapy and chemotherapy effects on critical normal tissues. Cancer 37: 1186-1200, 1976. 12. Phillips, T.L., Wharam, M.D., Margolis, L. W.: Modification of radiation injury to normal tissues by chemotherapeutic agents. Cancer 35: 1678-1684, 1975. 13. Presnov, M.A., Kanovalova, A.L., Romanova, L.F., Sofina, Z.P., Stetsenko, A.I.: Chemotherapy of transwith mouse cis-dichlorodiamplantable tumors mineplatinum(I1) alone and in combination with sarcolysis. Cancer Treat. Rep. 62: 705-712, 1978. 14. Rosenberg, B.: Possible mechanisms for the antitumor activity of platinum coordination complexes. Cuncer Chemotherapy Rep. 59: 589-598, 1975. 15. Rosenberg, B., Van Camp, L., Krigas, T.: Inhibition of cell division in Escherichia co/i by electrolysis products from a platinum electrode (letter). Nature (Lon-
August 1979, Volume 5, Number 8
don) 205: 698-699, 1965. 16. Rosenberg, B., Van Camp, L., Trosko, J.E., et al.: Platinum compounds: a new class of potent antitumor agents (letter). Nature (London) 222: 385-386, 1969. R.F., 17. Schenken, L.L., Burholt, D.R., Hagemann, Lesher, S.: The modification of gastrointestinal tolerance and response to abdominal irradiation by 120: 417-420, chemotherapeutic agents. Radiology 1976. 18. Taylor,
D.M., Tew, K.D., Jones, J.D.: Effects of cisdichlorodiimmineplatinum (II) on DNA synthesis in kidney and other tissues of normal and tumor-bearing rats. Europ. J. Cancer 12: 24S254, 1976. 19. Wiltshaw, E., Kroner, T.: Phase II study of cischlorodiammineplatinum (II) (NSC 119875) in advanced adenocarcinoma of the ovary. Cancer Treat. Rep. 60: 55, 1976. 20. Withers, H.R.,
Elkind, M.M.: Microcolony survival assay for cells of mouse intestinal mucosa exposed to radiation. Int. J. Radiat. Biol. 17: 261-267, 1970. 21. Yagoda, A., Watson, R.C., Kemeny, N., Borzell, W.E., Grabstald, H., Whitmore, W.F.: Diamminedichlorideplatinum II and cyclophosphamide in the treatment of advanced bladder cancer. Cancer 41: 2121-2130. 1978.
fnt. J. Rocliafion Owo/oi~\’ Biol. f’hys.,, Vol. 5, pp. 1417-1420 Pergamon Press Ltd., 1979. Printed in the U.S.A.
??Cis-Platinum
THE INTERACTION DIAMMINEDICHLOROPLATINUM
OF RADIATION AND CIS(II) IN INTESTINAL CRYPT CELLS-t
H. LUK, M.D.,* GLENDA Y. Ross, B.S., THEODORE M.D.,and LAWRENCE S. GOLDSTEIN, Ph.D.
KENNETH
L. PHILLIPS,
of Radiation Oncology, University of California, San Francisco, CA 94143, and SThe Claire Zellerbach Saroni Tumor Institute, Mount Zion Hospital, San Francisco, CA 94115
Department
The effect of radiation and cis-platinum in combination was studied in the intestinal crypt cell survival system of the LAF,mouse. The drug LDn,Jso was 22 mg/kg and the maximum tolerated dose (MTD)(LD,,) was 13 mg/kg. That dose caused 80% cell kill when given either 3 hrs after or 2 hrs before a dose of 1100 rad. When the MTD was given from -48 to +48 hrs relative to a dose of 1110 rad, survival fluctuated with minima at - 12 hrs, 0 and + 12 hrs. A radiation survival curve determined 2 hrs after an MTD drug dose was parallel to the control, but shifted to lower doses due to cell kill. The extrapolated D, was 280 rad, but the split dose survival ratio was only 1.3 compared to a control value of 7 at the same survival level. A repeat experiment with B,AF, mice yielded a survival ratio of 3 vs 6 for controls. Cis-platinum may reduce repair of radiation injury, as well as kill intestinal crypt cells. Cis-platinum,
Intestinal crypt cells, Maximum tolerated dose.
INTRODUCTION
METHODS
AND MATERIALS
II (cisDDP) is an anti-tumor agent currently used in the treatments of testicular, ovarian, bladder, and head and neck carcinomas, as well as other miscellaneous tumors, such as neuroblastomas and colon cancers.2~*,1”~21 Cis-DDP is a complex inorganic compound with platinum in the center and 2 chlorine and 2 ammonia atoms in the cis position. Its mode of action seems to be the inhibition of DNA synthesis by cross-linking DNA molecules and blocking mitosis at G,.“,14 Its cytotoxicity has been proven in many in viva and in vitro systems.“~4~s~‘3~1fi~‘X The cancer chemotherapeutic agents which have been extensively studied for modification of radiation effects on tumors and normal tissues include actinomycin D, Adriamycin, 5-fluorouracil, BCNU, cyclophosphamide, and bleomycin.‘O Recently cisDDP has been found to not only add to radiation cell kill in tumors, but also to act as a hypoxic cell sensitizer.’ In this study, we evaluate the response of intestinal crypt cells to different doses of radiation and cis-DDP, as well as to evaluate the different time intervals of administration of these two modalities.
IO-12 weeks, were used. They were housed 4-6 per cage, and were given laboratory chow and water ad libitum. One split dose experiment was carried out with B,AF, mice of similar age and source. Solutions of cis-DDP were prepared in water to allow injection of volumes of 0.01 ml/gm of body weight. The maximum tolerated dose (MTD or LD 0.0,7 the LDJ,, and the LDJ,,) of the cis-DDP were found by administering drug doses yielding IO-90% survival varying from 1 to 100% in groups of 10-15 mice. A 137Cs irradiator delivered a dose rate of 235 rad/minute. The mice were irradiated whole body in rotating lucite cages placed parallel to the axis of the linear radiation source and perpendicular to the beam. No anesthesia was used. Single radiation doses of 800 to 1800 rad were given in 200 rad increments. This group of mice was compared with a similar group which also received cis-DDP at the MTD 2 hrs prior to irradiation. Two experiments with single or split (3 hrs) radiation doses were also carried out 2 hrs after cis-DDP administration in order to determine the survival ratio, the ratio of
iThis investigation was supported by National Cancer
Cis-DDP was supplied by the Drug Development Branch of the Division of Cancer Treatment, National Cancer Institute in the form of clinical ampules.
Cis-platinum,
cis-diamminedichloroplatinum
Institute Research Grants CA17227 and CA20529 JDr. Luk is the recipient of an American Cancer Clinical Junior Faculty Fellowship.
Male
Society
1417
LAF,
mice,
age
1418
Radiation Oncology 0 Biology 0 Physics
number of surviving crypt cells per circumference for 2 fractions divided by the number for one fraction. Control survival ratios for similar cell numbers were used. Cis-DDP was given at the MTD at intervals of 48, 36, 24, 18, 12, 6, 2, or 0 hrs prior to or after a single dose of radiation of 1110 rad. The drug was administered at the MTD, 3/4 MTD, 1/2 MTD, or ‘14 MTD 2 hrs prior to or 3 hrs after a single radiation dose of 1100 rad. Four to six mice per data point were sacrificed by cervical dislocation 32/3 days after irradiation. The jejunum was removed from the animals, fixed in Tellyesniczky’s fixative, and processed for paraffin sectioning. Five micron sections were prepared from each specimen, stained with hematoxylin, phloxine, and safran, and scored for the number of regenerating crypts per circumference. These numbers were converted to crypt cells per circumference by the technique of Withers and Elkind.20
RESULTS Drug LD,,, determinations at 5 days and 60 days were 36 and 22 mgikg, respectively. The MTD of 13 mgikg yields less than 1% death. Fig. 1 demonstrates the radiation dose response of mouse intestinal crypt cells with or without prior administration of the MTD of cis-DDP. There is marked enhancement of the radiation effect with the addition of the drug at all radiation dose levels, with a shift of the curve to the left side. There does not appear to have been a change in the slope of the curve, however. Extrapolation to obtain the D, yields a value of 280 rad, as compared to 400 rad for controls, when correction for 80% cell kill by drug alone is made. The enhancement effects of cis-DDP at 4 different drug dose levels are shown in Fig. 2. The MTD yields an 80 % cell kill. There is more destruction of the intestinal crypt cells at dose levels of )/4 MTD and I/Z MTD, than at the dose of l/4 MTD, where the response is similar to the radiation only control group. There does not appear to have been a significant difference whether drug is given 2 hrs prior to or 3 hrs after irradiation. The effects of MTD doses of cis-DDP spaced +48 hrs relative to a single dose of radiation (1110 rad) are shown in Fig. 3. There is a decrease in the intestinal crypt cell survival when radiation and cis-DDP are given simultaneously. The effects of cis-DDP on radiation do not seem to diminish when the drug is given more than 2 hrs before or after radiation. The dips in the surviving crypt counts at 12 and 36 hrs before and 12 and 48 hrs after radiation may be related to the partial synchrony caused by either agent. Split dose studies carried out in LAF, mice
August 1979, Volume 5, Number 8
1000
r 0
‘=7c8
V 13 mg/Kg
600
1200 DOSE,
1600
-
RAD
Fig. 1. Radiation survival curves for intestinal crypt cells exposed to 13Ts gamma rays alone (0) or 2 hrs following (V) 13 mgikg of cis-DDP. 200
IOC
5a
lo-3.25
6.50
9.75
13.00
DOSE, mg/Kg
Fig. 2. Drug survival curves for intestinal crypt cells with cis-DDP in increasing doses given 2 hrs before (0) or 3 hrs after (0) 1100 rad of 13Ts gamma rays.
yielded survival ratios of 7 for control animals (cell number for single exposure 12) and 1.3 for animals pretreated with 0.75 MTD of cis-DDP (cell number for single exposure 7). A second experiment with BBAF, mice yielded survival ratios of 6 for controls and 3 for cis-DDP (single dose cell number 15 and 8, respectively).
Interaction
CIS-PLATINUM,
1000
of radiation and cis-platinum 0 LUK et 01.
13 mg/Kg
I
r
TIME
OF DRUG
INJECTION.
HR
Fig. 3. Crypt cell survival (0) as a function of time between administration of cis-DDP (13 mgikg) and 137Cs gamma rays (1110 rad).
DISCUSSION Cis-DDP is a potent cytotoxic agent, notwithstanding the fact that it was discovered by serendipity.‘” Renal damage has been identified as the major toxic effect.s The gastrointestinal toxicity in man includes marked nausea and vomiting, not usually relieved by antiemetics. Taylor, Tew and Jones’* showed that in rats the rate of DNA synthesis in the intestine 26 hrs after treatment with 6 mg cis-DDP per kg body weight was reduced to one tenth or less of the control level. With these facts in mind, the combined effects of radiation and cis-DDP on the intestinal mucosa needs to be examined since this drug is receiving greater recognition. The rather low LD5,j5 (36 mg/kg) and the 80 % cell kill caused by the MTD added to 1110 rad indicates that cisDDP alone is quite cytotoxic to intestinal crypt cells.
1419
Schenken et al. I7 studied the combined effects of radiation and methotrexate, cyclophosphamide, Adriamycin, and BCNU on the jejunum in mice, and concluded that excessive gastrointestinal toxicity may result if aggressive chemotherapy is closely spaced with radiation exposure for the treatment of abdominal neoplasms. Phillips et al. ‘* studied the intestinal microcolony survival in LAF, mice using radiation and actinomycin D, Adriamycin, BCNU, bleomycin, or cyclophosphamide, and found dose effect factors (DEF) ranging from 3.3 for Adriamycin given 2 days before radiation to 0.93 for actinomycin D given 7 days after radiation. The authors recommended the use of mouse model systems to test any cancer chemotherapeutic agents to be used in combination with radiation in humans. Phillips and Fu” further discussed the problems of quanitification of combined radiation and chemotherapy effects on normal tissues. There is still very limited information in terms of clinical experiences and perhaps more data accumulated in experimental animals. A dose effect factor between 1.1 and 1.8 has been found for most of the chemotherapeutic agents studied. In this study the DEF for cis-DDP at MTD is 1.3 for jejunal crypt cells at 2 hrs prior to irradiation (Fig. 1). However, our time interval study shows that the DEF may be greater when cis-DDP is given simultaneously with radiation. This should caution the clinicians that a markedly reduced dose of radiation or cis-DDP may be necessary when normal intestines are included in the radiation portal. The data are inconclusive concerning the effect of cis-DDP on repair of radiation injury, although the D, is slightly reduced and the split dose studies showed a lower survival ratio when cis-DDP was used. Complete split dose studies are underway for a wide range of time intervals. Interference with repair could be important in terms of normal tissue damage.
REFERENCES Douple,
Richmond, R.C., Logan, M.E.: E.B., Therapeutic potentiation in a mouse mammary tumor and an intracerebral rat brain tumor by combined treatment with cis-dichlorodiammineplatinum (II) and radiation. J. Clin. Hemat. 0~01. 7: M-603, 1977. Einhom, L.H., Donohue, J.: Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Ann. Internal Med. 87: 293-298, 1977. Gale, G.R., Atkins, L.M., Meischen, S.J., Smith, J.B., Walker, Jr., E.M.: Chemotherapy of advanced L1210 leukemia with platinum compounds in combination with other antitumor agents. Cancer Treat. Rep. 61: 445-450, 1977.
4. Ghanta. V.K.. Jones. M.T., Woodard, P. A., Durant, Cis-dichlorodiammineplatJ.R., ‘Hiramoto, R.N.: inum(II) chemotheapy in experimental murine mYelOma MOPC 103E. Cancer Research 37: 771-774, 1977. Heinen, E., Bassleer, R.: Cytological and cytochemical analysis of the effects of cis-dichlorodiaminoplatinum (II) on chick fibroblasts cultivated in I’itro. Chemotherapy 22: 253-261, 1976. Heinen, E., Bassleer, R.: Mode of action of cisdichlorodiammineplatinum (II) on mouse ehrlich ascites tumor cells. Biochem. Pharmac. 25: 1871-1875, 1976. Higby, D.J., Wallace, H.J., Albert, D.J., et al.: Diaminodichloroplatinum: a phase I study showing responses in testicular and other tumors. Cancer 33:
1420
1219-1225, 8. Hill, J.M., studies of treatment
Radiation Oncology 0 Biology 0 Physics
1974. Loeb, E., MacLellan, platinum coordination of various malignant
A., et ul. : Clinical compounds in the diseases. Cancer
Chemotherapy Rep. 59: 647-659, 1975. 9. Madias, N.E., Harrington, J.T.: Platinum ity. Amer. J. Med. 65: 307-314, 1978.
nephrotoxic-
10. Phillips, T.L.: Chemical modification of radiation effects. Cancer 39: 987-999, 1977. 11. Phillips, T.L., Fu, K.K.: Quantification of combined radiation therapy and chemotherapy effects on critical normal tissues. Cancer 37: 1186-1200, 1976. 12. Phillips, T.L., Wharam, M.D., Margolis, L. W.: Modification of radiation injury to normal tissues by chemotherapeutic agents. Cancer 35: 1678-1684, 1975. 13. Presnov, M.A., Kanovalova, A.L., Romanova, L.F., Sofina, Z.P., Stetsenko, A.I.: Chemotherapy of transwith mouse cis-dichlorodiamplantable tumors mineplatinum(I1) alone and in combination with sarcolysis. Cancer Treat. Rep. 62: 705-712, 1978. 14. Rosenberg, B.: Possible mechanisms for the antitumor activity of platinum coordination complexes. Cuncer Chemotherapy Rep. 59: 589-598, 1975. 15. Rosenberg, B., Van Camp, L., Krigas, T.: Inhibition of cell division in Escherichia co/i by electrolysis products from a platinum electrode (letter). Nature (Lon-
August 1979, Volume 5, Number 8
don) 205: 698-699, 1965. 16. Rosenberg, B., Van Camp, L., Trosko, J.E., et al.: Platinum compounds: a new class of potent antitumor agents (letter). Nature (London) 222: 385-386, 1969. R.F., 17. Schenken, L.L., Burholt, D.R., Hagemann, Lesher, S.: The modification of gastrointestinal tolerance and response to abdominal irradiation by 120: 417-420, chemotherapeutic agents. Radiology 1976. 18. Taylor,
D.M., Tew, K.D., Jones, J.D.: Effects of cisdichlorodiimmineplatinum (II) on DNA synthesis in kidney and other tissues of normal and tumor-bearing rats. Europ. J. Cancer 12: 24S254, 1976. 19. Wiltshaw, E., Kroner, T.: Phase II study of cischlorodiammineplatinum (II) (NSC 119875) in advanced adenocarcinoma of the ovary. Cancer Treat. Rep. 60: 55, 1976. 20. Withers, H.R.,
Elkind, M.M.: Microcolony survival assay for cells of mouse intestinal mucosa exposed to radiation. Int. J. Radiat. Biol. 17: 261-267, 1970. 21. Yagoda, A., Watson, R.C., Kemeny, N., Borzell, W.E., Grabstald, H., Whitmore, W.F.: Diamminedichlorideplatinum II and cyclophosphamide in the treatment of advanced bladder cancer. Cancer 41: 2121-2130. 1978.