INT. J . HYPERTHERMIA,

1992, VOL. 8,

NO.

6, 783-794

Whole-body hyperthermia as an adjuvant to treatment with platinum complexes with or without etanidazole in mice bearing the Lewis lung carcinoma or the FSaLL fibrosarcoma B. A. TEICHER*, T. S. HERMAN, K. MENON and T. T. KORBUT Dana-Farber Cancer Institute and Joint Center for Radiation Therapy, 44 Binney Street, Boston, MA 02115, USA Int J Hyperthermia Downloaded from informahealthcare.com by Chulalongkorn University on 12/26/14 For personal use only.

(Received 18 May 1992; accepted 22 May 1992)

The response of S.C. primary and metastatic Lewis lung carcinoma to five antitumour platinum complexes with or without tolerable whole-body hyperthermia (60min to reach temperature then 60 min at 42°C) was examined. The whole-body hyperthermia treatment produced about 2.8 days of tumour growth delay in the S.C. tumours. The addition of whole-body hyperthermia to treatment with each of the platinum complexes was well tolerated by the animals and increases of 1.6-2.0-fold in tumour growth delay resulted with the combined treatment compared with the platinum complexes alone. The combination of etanidazole (1 g/kg) and the platinum complexes followed by wholebody hyperthermia produced marked increases in tumour growth delay ranging from 2.5- to 3 ~6-foldover the growth delays obtained with the platinum complexes alone. FSaLLC tumour cell survival and bone marrow CFU-GM experiments indicated that local hyperthermia (43"C, 30 min) produced greater potentiation of the cytotoxicity of three platinum complexes than did whole-body hyperthermia (42"C, 60 min). Only the complete treatments including whole-body hyperthermidetanidaole and the platinum complexes were effective in significantly reducing the numbers of lung metastases formed from S.C. primary tumours. Serum urea nitrogen and creatinine levels were monitored over a time-course post-treatment. Although some treatment combinations caused elevations in these normal tissue parameters by day 12 post-treatment both serum urea nitrogen and serum creatinine returned to the levels of the untreated control animals. Key words: Whole-body hyperthermia, platinum complexes, etanidazole, lung metastases

1. Introduction

For many patients cancer is or becomes a disseminated disease. For these patients three main treatment modalities are currently available: (1) radiation therapy, (2) chemotherapy and (3) hyperthermia. Although the parameters for optimal radiation therapy of various body segments are well established, and refinements in treatment with chemotherapy are a continuing major endeavour, there has not been a concerted preclinical effort devoted to developing therapeutically optimized whole-body hyperthermia/chemotherapy combinations. Modern clinical studies of whole-body hyperthermia (WBH) have spanned 15 years (Herman e? al. 1982, Ostrow er al. 1982, Magin 1983, Van der Zee ef al. 1983, Bull 1984, Cronaw et al. 1984, Robins 1984, Robins et al. 1988a,b,c, 1989a,b, Dahl 1987, Engelhardt 1987, 1988, Meyer et al. 1989). These trials have, in general, demonstrated' a relatively high percentage of responses, although these responses tend to be short-lived and were associated with considerable toxicity. Essentially no cures with WBH and radiation therapy or chemotherapy, however, have been observed. It has been well established that the 2-nitroimidazole radiosensitizing agents such as *To whom correspondence should be addressed. 0265-6736/9? 53.00 01992 Taylor & Francis Ltd

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etanidazole can also act as selective cytotoxic drugs for hypoxic cells (Adams et al. 1984, Chaplin et al. 1986, Frank 1986, Hill 1986). In addition, these compounds, which are said to mimic the effect of oxygen in cells, have been shown to enhance the cytotoxicity of several antitumour alkylating agents including L-PAM, cyclophosphamide, BCNU, and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea in virro and in vivo. This phenomenon has been termed chemosensitization (Clement et al. 1980, Fowler 1985, Teicher et al. 1991). The presence of hypoxic cells in solid tumours may account for the preferential effect, since chemosensitization in vitro occurs only when cells are exposed to the 2-nitroimidazole under hypoxic conditions, i.e. conditions in which reduction of misonidazole through formation of oxygen-mimicking free radicals can occur. For these reasons we examined the ability of the 2-nitroimidazole etanidazole to act as a chemosensitizer (or modulator) of a series of antitumour platinum complexes. The current study examines the response of primary and metastatic Lewis lung carcinoma to five antitumour platinum complexes with or without tolerable WBH (42"C, 60 min). Serum creatinine changes over time are used as an indicator of normal tissue effects. The ability of etanidazole to act as a modulator of the platinum complexes is also explored. 2. Materials and methods

2.1. Drugs Cis-diamminedichloroplatinum(I1) (CDDP) and carboplatin (Carbo) were gifts of Dr Alfred Crosswell, Bristol-Myers-Squibb, Inc., Wallingford, CT. D,L-Tetraplatin (D,LTetra) was a gift of Dr Patrick McGovern, Upjohn Co., Kalamazoo, MI. Platinumtetrachloro(rhodamine 123), (PtC14(Rh-123),) and platinumtetrachloro(fast black), (RCl,(fast black),) were prepared in our laboratory by the reaction of 1 mol equivalent K2RC14with 2 mol equivalents of the cationic dyes rhodamine-123 or fast black. Etanidazole was a gift of Dr Nancita Lomax, NCI, National Institutes of Health, Bethesda, MD. 2.2. Tumour Lewis lung tumour (Shipley er al. 1975, Stanley et al. 1977, Steel et al. 1978) is carried in male C57BL mice (Taconic Farms, Germantown, NY). The FSaLL fibrosarcoma (Rice et al. 1980) adapted for growth in culture (FSaLLC) (Teicher and Rose 1984) is carried in male C3HlFe.l mice (Jackson Laboratories, Bar Harbor, ME). For experiments, 2 x lo6 tumour cells prepared from a brei of several stock tumours will be implanted i.m. into the legs of 8-10-week old male mice. 2.3. Tumour growth delay When tumours were about 100 m3in volume (about 1 week after tumour cell implantation) the animals were injected i.p. with single doses of each of the platinum complexes. The doses were: CDDP, 10 mg/kg; Carbo, 50 mg/kg; D,L-tetraplatin, 15 mg/kg; PtgCl4(Rh-123),, 50 mg/kg and PtCl,(fast black),, 100 mg/kg (Herman et al. 1988a,b, Teicher et al. 1989a,b). WBH was administered by radiant heating (Enthermics, Menomonee Falls, WI)bringing the core temperature of the animals to 42°C over 60 min then maintaining that core temperature at 42°C for 60 min. During WBH the animals were anaesthetized with ketamine (0.05 mg/g) and xylazine (0.05 mg/g) administered i.p. The core temperatures of representative animals in the radiant heating chambex were monitored during each treatment using Sensortech temperature monitoring systems. Only six animals were treated in the box at any time. Prior experiments demonstrated that the core temperatures of the animals

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were controllable to 42 *0.4"C in the central region of the box. Animal position assignment in the box was random. WBH was administered as a single dose on the day of drug treatment. Animals not receiving WBH were anaesthetized in the same way as WBH-treated animals, and were maintained at a core temperature of 37°C using heat lamps. For tumour growth delay assays, the day on which the tumour in each individual animal reached 500 mrd in volume (5 times the initial volume) was determined, and the mean for that treatment group f the standard error of the mean was compared with the control and other treatment groups in a two-tailed t-test (Schabel et al. 1979). Each treatment group had six animals, and the experiment was carried out three times. 2.4. Metastases On day 20 post-tumour cell implantation, lungs were removed and fixed in Bouin's solution. Metastases on the external surfaces of the lungs were counted by eye (Teicher et al. 1988). 2.5. Tumour cell survival assay When FSaLLC tumours reached a colume of approximately 100 mm' (about 1 week after tumour cell implantation), the animals were treated with WBH (42"C, 60 min) or with local hyperthermia (43"C, 30 min) to the tumour-bearing limb. Local hyperthermia was performed by immersing the tumour-bearing limb in a 44°C water-bath (Herman et al. 1988b, Teicher et al. 1989b). The time required for the tumours to reach 43°C was less than 5 min. Mice were killed 24 h after treatment, to enable full expression of drug cytotoxicity and repair of potentially lethal damage. The tumours were excised under sterile conditions in a laminar flow hood and minced to a fine brei using two scalpels. Four tumours were pooled for each treatment group. Approximately 300 mg tumour brei was used to make each single-cell suspension. All reagents were sterilized with 0 -22-pm Millipore filters and were added aseptically to the tumour cells. Each sample was washed in 20 ml a-MEM, after which the liquid was gently decanted and discarded. The samples were resuspended in 450 units collagenase/ml (Sigma, St Louis, MO) and 0.1 mg DNase/ml (Sigma) and were incubated for 10 min at 37"C, following which the samples were filtered through two layers of sterile gauze. The samples were washed twice, then resuspended in a a-MEM supplemented with 10% fetal bovine serum. These single-cell suspensions were counted and plated in duplicate at three different cell numbers for the colony-forming assay. No significant difference was observed in total cell yield from the pooled tumours in any treatment group. After 1 week the plates were stained with crystal violet and colonies of > 50 cells were counted. The untreated tumour cell suspensions had a plating efficiency of 10-16%. The results are expressed as the surviving fraction ( f SE) of cells from treated groups as compared with untreated controls (Teicher et al. 1987a,b). 2.6. Bone murrow toxicity Bone marrow was taken from the same animals used for the tumour excision assay. A pool of marrow from the femurs of two animals was obtained by gently flushing the marrow through a 23-gauge needle and the CFU-GM assay was carried out as previously described (Teicher et al. 1987a,b). Colonies of at least 50 cells were scored on an Acculite colony counter (Fisher Scientific, Springfield, NJ). The results of three experiments, in which determinations for each group were made in duplicate at three cell concentrations, were averaged. The results are expressed as the surviving fraction from treated groups as compared with untreated controls.

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2.7. Serum urea nitrogen and creatinine determinations Serum urea nitrogen (BUN) and creatinine was determined on days 8, 12 and 19 posttumour cell implantation in animals treated with each of the platinum complexes, or with WBH and the platinum complexes on day 7. BUN determinations were made using diagnostic kit 550 and creatinine determinations were made using diagnostic kit 555 from Sigma Chemical Co. (St Louis, MO). The data are presented as BUN in mg/dl in each treatment group, and change in serum creatinine compared with levels found in untreated control animals bearing Lewis lung tumours.

3. Results The Lewis lung carcinoma is a relatively chemotherapy-resistant tumour which spontaneously metastasizes to the lungs of the host from primary S.C.implants. The Lewis lung model therefore allows assessment of the response to treatment of both primary and systemic disease. The whole-body hyperthermia (WBH) treatment (60 min to temperature (42°C) then 60 min at 42°C) produced about 2.8 days of tumour growth delay in the S.C.tumour compared with untreated controls (Table 1). When each of the five platinum complexes was administered i.p. at tolerable doses to the tumour-bearing animals growth delays of 5-7 days in the primary implant resulted. The addition of WBH following drug administration to treatment with each of these platinum complexes was well tolerated by the animals and increases of 1.6-2.0-fold in tumour growth delay resulted with the combined treatment compared with the platinum complexes alone. The addition of etanidazole (1 g/kg) administered i.p. just prior to administration of the platinum complexes similarly resulted in 1.5-2 .O-fold increases in tumour growth delay compared with the platinum complexes alone. The combination of etanidazole (1 g/kg) and the platinum complexes followed by WBH produced marked increases in tumour growth delay ranging from 2.5- to 3 e6-fold over the growth delays obtained with the platinum complexes alone. The effect on FSaLLC tumour cell survival and bone marrow CFU-GM survival of WBH (42"C, 60 min) or local hyperthermia (43"C, 30 min) to the tumour-bearing limb along three of the platinum complexes was assessed (Figure 1). Treatment of FSaLLC tumour-bearing animals with 10 mg/kg of CDDP resulted in a surviving fraction of 0 - 16 for the tumour cells and of 0.65 for the bone marrow CFU-GM derived from the femur of the tumour-bearing limb. Adding WBH to treatment with CDDP resulted in a 2-fold increase in tumour cell killing, while hyperthermia locally to the tumour-bearing limb resulted in a 100-fold increase in tumour cell killing compared with CDDP alone. There Table 1. Growth delay of the Lewis lung carcinoma produced by Pt-containing anticancer drugs f WBH with or without ETA addition of WBH to treatment. Turnour growth delav. davsa Treatment and dose Controls CDDP~ Carboplatin D,L-Tetraplatin PtCId(Rh-123)Z PtCl,(fast black),

(rng/kg)

Alone -

10 50 15

50 100

6.7zt1.2 5.2kl.l 5.5k0.9 5.3*1*0 5.6*1*1

+ETA (1 g/kg) 0.3iz0.5 12.5&1*4 9.9jz1.2 8-0&1.0

9.4zk1.7 11.2&1.5

+

WBH' +ETA/WBH 2.8&0.7 3.5&0*8 17.2jz1.7 10.9&1*5 16.9zk1.8 9*1&1.4 9 * 6 & 1 * 0 13.9zt1.5 19.2jz1.8 10.0&1.5 1 1 * 3 & 1 * 2 19.4&1.9

aTumours were grown S . C . in the flanks of animals and were about 100 rnm3 at the time of treatment. Treatment response was monitored by turnour volume measurements. bAll drugs were injected i.p. first prior to initiation of heating in those animals receivng whole-body hyperthermia. WBH was produced by radiant heating. Animals were anaesthesized then brought to a core temperature of 42°C over 60 min. Animals not receiving WBH were anaesthesized and maintained at 37°C.

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z '

0

0

E

BM CFU-GM

2l & ' 0

i

p: O'

2

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001

NORM WBH LUCAL

CDDP

NORM WBH LOCAL

CARBO

NORM WBH LOCAL

D.L?FIRA

Figure 1. Survival of FSaLLC tumour cells: W, from tumours treated in vivo and of bone marrow CFU-GM El from the femurs of the tumour-bearing limb after treatment with CDDP (10 mg/kg), carboplatin (50 mg/kg) or D.L-tetraplatin (15 mg/kg) alone or in combination with WBH (42"C, 60 min) and with local hyperthermia (43"C, 30 min). Bars represent SEM.

was very little change in the toxicity of CDDP to the bone marrow CFU-GM with the addition of either hyperthermia treatment. Carboplatin (50 mg/kg) produced a surviving fraction of 0.17 for the tumour cells and a surviving fraction of 0.19 for the bone marrow CFU-GM from the femur of the tumour-bearing leg. The addition of WBH to treatment with carboplatin resulted in a 2 -4-fold increase in tumour cell killing while local hyperthermia increased tumour cell killing by 5 e2-fold compared with carboplatin alone. The increase in the killing of bone marrow CFU-GM with the addition of hyperthermia to carboplatin was less than the increase in the killing of tumour cells amounting to 3.8-fold with local hyperthermia. D,L-Tetraplatin (15 mg/kg) was more toxic towards bone marrow CFU-GM than towards FSaLLC tumour cells. The surviving fraction for FSaLLC cells with D,L-tetraplatin was 0-20, while for the bone marrow CFU-GM the surviving fraction was 0.052. The addition of WBH to treatment with D,L-tetraplatin resulted in a 1 e4-fold increase in tumour cell killing and the addition of local hyperthermia to treatment with D,L-tetraplatin resulted in a 1 .&fold increase in tumour cell killing compared with the drug alone. WBH increased the killing of bone marrow CFU-GM by D,L-tetraplatin by 4-fold and local hyperthehia increased the killing of bone marrow harvested from the femur of the tumour-bearing leg by 5.8-fold. Lungs were harvested from the animals described in Table 1 and metastases on the external surfaces of the lungs were counted (Figure 2). Untreated control animals and animals treated with WBH, etanidazole (1 g/kg) or etanidazole/WBH showed no differences in the number of lung metastases (mean = 15). Each of the five platinum complexes produced a small effect on the number of lung metastases so that the mean numbers were 12 or 13, and the addition of etanidazole to treatment with the platinum complexes did not alter those numbers. WBH in addition to treatment with the platinum complexes produced some diminution in the number of lung metastases, resulting in mean numbers of metastases from nine to 11. The combination of etanidazole and each of the platinum complexes followed by WBH was most effective in reducing the number of lung metastases so that there was a mean number of six lung metastases when the treatment included CDDP, PtCl,(Rh-123), or PtCl,(fast black),, a mean number of eight lung metastases when the treatment included carboplatin and a mean number of 10 lung metastases when the treatment included D,L-tetraplatin. Serum BUN and creatinine levels were used as an indication of the renal damage caused

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788

by treatment with each of the platinum complexes alone or in combination with WBH. The serum BUN gradually rose in the untreated tumour-bearing animals over time from day 8 to day 19 (Figure 3). These untreated control animals survive for 21-25 days posttumour implantation. Only treatment with D,L-tetraplatin resulted in a significant increase in serum BUN. The addition of WBH to treatment with each of the five platinum complexes did not alter the serum BUNS compared with untreated tumour-bearing animals. Treatment with carboplatin or PtC14(Rh-123), resulted in an acute rise in serum creatinine, while treatment with CDDP and D,L-tetraplatin produced measurable changes in serum creatinine as determined 5 days post-treatment. By day 12 post-treatment, however, serum creatinine levels were the same in both treated and control animals. WBH alone resulted acutely in a 2.2-fold increase in serum creatinine, and the addition of the platinum complexes to WBH did not significantly change the serum creatinine from that obtained with WBH alone. Treatment with carboplatin and PtCl,(fast black), in combination with WBH

w"l I

I

RDmg

I

R WBH

Figure 2. Mean numbers of lung metastases on day 20 post-s.c. tumour implantation on the external surfaces of the lungs of C57BL mice bearing S.C.Lewis lung tumours after treatment with CDDP (10 mglkg), carboplatin (50 mg/kg), D,L-tetraplatin (15 mglkg), PtC14(Rh-123), (50 mglkg), PtC14(fast black), (100 mglkg) alone, along with WBH (42"C, 60 min), in combination with etanidazole (1 glkg) or along with both etanidazole and WBH. Bars represent SEM .

-

*,rut

Bkk19

?

7

2

B

(I

Days Poot Tumor Cell Xmplrntation

Figure 3. BUN measurements determined on days 8, 12 and 19 (treatments were administered on day 7) post-tumour implantation for untreated controls (a),WBH treated (O), CDDP (10 mgkg) treated m, carboplatin (50 mglkg) treated 0 ,D,L-tetraplatin (15 mglkg) treated (A),Ptc14(Rh-123)2 (50 mglkg) treated (A) or RCl,(fast black), (100 mg/kg) treated (*) alone or in combination with WBH. Bars represent SEM.

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Figure 4. Serum creatinine measurements determined on days 8, 12 and 19 (treatments were administered on day 7) post-tumour implantation for untreated controls (a),WBH treated (D), CDDP (10 mg/kg) treated (m, carboplatin (50 mg/kg) treated (O), D.L-tetraplatin (15 mg/kg) treated (A), PtCI4(Rh-123), (50 mg/kg) treated (A) or PtC14(fast black), (100 mg/kg) treated (*) alone or in combination with WBH. Bars represent SEM.

resulted in an increase in serum creatinine which was measurable 5 days post-treatment. By 12 days post-treatment serum creatinine returned to the levels of the untreated controls. 4. Discussion Although a substantial literature exists describing the effects of local hyperthermia on the antiturnour activity of a variety of chemotherapeutic agents, the literature on the area of WBH and chemotherapy in tumour model systems is quite sparse (Rose et al. 1979, Robins 1984, Hinkelbein et al. 1984, Mella et al. 1987, Steeves et al. 1987, Bull er al. 1988, Robins et al. 1988, Wondergem et al. 1988a,b, 1989, 1991, Baba et al. 1989, 1991, Ohno et al. 1991). Rose et al. (1979) examined the effects of very mild WBH on the antitumour activity of eight drugs in five tumour systems. No effect of WBH was observed in this study. Robins et al. (1988) examined lonidamine f total-body irradiation f WBH in AKR rnurine leukaemia and obtained very positive results with the complete treatment combination. In dogs, WBH has been examined in combination with CDDP (Riviere et af. 1986, 1990, Page et a f . 1988), carboplatin (Riviere et al. 1986, 1990, Page et al. 1988), adriamycin (Price et al. 1990, Wilke et al. 1991, Novotney et al. 1991, Page et al. 1991a), melphalan (Page et af. 1991b), DFMO (Klein et al. 1987), lonidamine (Price et al. 1988, 1989), and 5-fluorouracil (Daly et al. 1982). Several of these studies indicated potential usefulness of chemotherapy/WBH for human trials. The tumour systems which we used for this study were the rnurine solid tumour FSaLLC fibrosarcoma chosen because sarcomas have often been treated and respond to WBH, and the Lewis lung carcinoma which allows assessment of the response of systemic disease to treatment. Because in WBH regimens both the chemotherapy and the heat are delivered systemically, it is critical to determine, as accurately as possible, in the preclinical setting potential sites of normal tissue toxicity of these treatment combinations. Wondergem et al. (1988a,b, 1989) examined the effect of WBH on CDDP-induced renal toxicity and antiturnour activity using a F344 rat model. Renal injury at 5 and 14 days after treatment was evaluated using animal mortality, renal functional assays (blood urea nitrogen, creatinine), and histopathological methods. WBH (120 min at 4 1 ~ 5 ° C )enhanced both antitumour effects and toxic side-effects. The latter included increased mortality, increased blood urea nitrogen and creatinine levels, and increased renal damage. After simultaneous treatment with WBH and CDDP, thermal enhancement ratios (TER) for renal damage

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between 2 and 3 -0were calculated. There was no qualitativedifference in tubular damage between the rats treated with CDDP alone or those treated with CDDP combined with WBH. However, at a fixed CDDP dose, damage in the combined treatment modality group was significantly greater than in the CDDP-only treated group. In the same model system, Bull e? al. (1988) found that when WBH was induced 45 min after CDDP administration, a significantly increased tumour growth delay was noted beyond that achieved by either treatment modality alone. The combination of WBH and CDDP treatments, however, produced an unacceptable increase in renal injury. 0-b-hydroxyethy1)-rutoside administration was found to effectively block the renal injury without interfering with the antitumour efficacy of the combined regimen. Wondergem et al. (1988a,b) also examined the effects of various anaesthetics on CDDPinduced renal and intestinal toxicities at 37°C and at 41 -5°C in the F344 rat model. When applied simultaneously with CDDP administration, WBH (120 min at 41 -5°C) increased the CDDP-induced toxicity as indicated by the thermal enhancement ratio of between 2 1 and 2.7 for the LD,, values. With combined WBH CDDP treatment the effect of anaesthetics on CDDP-induced toxicities was generally similar to that observed at 37°C. Mella et al. (1987) investigated morbidity and mortality of combined CDDP and hyperthermia. BD IX rats were given 4 mg/kg CDDP i.p. and waterbath hind leg heating (44"C, 60 min) with resultant WBH. Cardiac blood and histopathological sections of kidney, small intestine and liver were examined in rats sacrificed 2, 3 and 5 days after treatment along with examination of femur bone marrow 5 days after treatment. In a separate experiment the effect of WBH on renal function was tested. The most significant finding was a marked increase in CDDP-induced renal damage by WBH, expressed as elevated creatinine levels and quantitatively enhanced proximal tubular necrosis. To maximize therapeutic gain Baba et al. (1989) studied the timing sequence of WBH and CDDP. Normal tissue injury as well as growth of a S.C. transplanted fibrosarcoma were measured in F344 rats treated with variable schedules of WBH and CDDP. Simultaneous application of CDDP (2 mg/kg i.v.) with WBH (120 min at 41.5"C) resulted in severe renal injury, body weight loss, and mortality; while sequential use of the modalities caused minimal to no toxicity. CDDP or WBH alone produced only minimal tumour growth delay, whereas supraaddititive antitumour effects occurred with all tested schedules of CDDP combined with WBH. In the current study we found that WBH (42"C, 60 min) and etanidazole (1 g/kg) were approximately equally effective modulators of the antitumour activities of each of the five platinum complexes. Treatment with the combination of etanidazole and WBH, along with the platinum complexes, produced the greatest enhancement in tumour growth delay. It is interesting that WBH was not as effective in increasing tumour cell killing with 42"C, 60 min as local hyperthermia (43°C 30 min). This may be due to greater heterogeneity of temperature achieved in tumours under WBH conditions than with local hyperthermia. Neither WBH nor etanidazole was a very effective addition to single doses of the platinum complexes in the treatment of systemic disease as determined by numbers of lung metastases arising from S.C. primary tumour implants. However, the combination of the two modulators and the platinum complexes was more effective in reducing the number of lung metastases, although metastatic disease was still present in all of the animals. Irreversible renal toxicity due to heavy metal poisoning in a major concern with WBH and platinum-containing drugs. We have used measurements of blood urea nitrogen and serum creatinine as estimates of renal function. WBH did not alter the effect of the platinum complexes on BUN while the platinum complexes did not significantly alter the effect of WBH on the serum creatinine. Serum creatinine levels returned to normal by 12 days after each of the treatments. These results differ in some respects from those obtained in the Fischer 344 rat. These differences may be due to differences in the sensitivity of

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a

5

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Whole-body hyperthermia and Pt complexes

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the host animals to platinum-induced renal damage. Under normothermic conditions the Fischer 344 rat can maximally tolerate 8 mg/kg CDDP while the C3H mouse can tolerate 10 mg/kg CDDP. It is likely that in the clinic supportive care such as fluid administration would be used to protect patients against the renal toxicity of these treatments. Overall, our results indicate that WBH is an effective modulator of the antitumour activity of platinum anticancer drugs and that further investigation of these combinations is warranted.

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Acknowledgement This work was supported by NIH grant ROl-CA50174. References ADAMS,G. E., AHMED,I., SHELDON, P. W. et al., 1984, Radiation sensitization and chemopotentiation: RSU-1069, a compound more effective than misonidazole in vitro and in vivo. British Journal of Cancer, 49, 5571-5577. BABA,H., SIDDIK,Z. H., STREBEL, F. R.,JENKINS,G. N. and BULL,J. M. C., 1989, Increased therapeutic gain of combined cis-diamminedichloroplatinum(n)and whole body hyperthermia by optimal heat/drug scheduling. Cancer Research, 39, 7041-7044. R.A., OHNO,S. and BULL, BABA,H., STEPHENS, L. C., STREBEL,F. R.,SIDDIK,Z. H., NEWMAN, J. M. C., 1991, Protective effect of ICRF-I87 against normal tissue injury induced by adriamycin in combination with whole body hyperthermia. Cancer Research, 51,3568-3577. BULL,J. M., 1984, A review of systemic hyperthermia. Frontiers in Radiation Therapy and Oncology, 18, 171-176. F. R., SUNDERLAND, B. A,, BULGER,R. E., EDWARDS,M., SIDDIK, BULL,J. M. C., STREBEL, Z. H. and NEWMAN, R. H., 1988, 0-0-Hydroxyethy1)-rustoside-mediated protection of renal injury associated with cis-diamminedichloroplatinum(I1)lhyperthermia treatment. Cancer Research, 48, 2239-2244. CHAPLIN, D. J., DURAND, R. E., STRATFORD, I. J. and JENKINS, T. C., 1986, The radiosensitizing and toxic effects of RSU-1069 on hypoxic cells in a murine tumor. International Journal of Radiation Oncology, Biology and Physics, 12, 1091-1095. J. J., GORMAN, M. S., WODINSKY, I., CATANE, R. and JOHNSON, R. K., 1980, EnhanceCLEMENT, ment of antitumor activity of alkylating agents by the radiation sensitizer misonidazole. Cancer Research, 40, 4165-4172. CRONAW, L. H., Jr, BOURKE,D. L. and BULL,J. M., 1984, General anethesia for whole-body hyperthermia. Cancer Research (Suppl.), 44, 4873s-4877s. DAHL,O., 1987, Interaction of hyperthermia and chemotherapy. Recent Results in Cancer Research,. 107, 157-169. DALY,J. M., SMITH,G., FRAZIER, 0. H., DUDRICK, S. J. and COPELAND, E. M., 1982, Effects of systemic hyperthermia and intrahepatic infusion with 5-fluorouracil. Cancer, 49, 112-1 15. ENGELHARDT, R., 1987, Hyperthermia and drugs. Recent Results in Cancer Research, 104, 136-203. ENGELHARDT, R . , 1988, Summary of recent clinical experience in whole-body hyperthermia combined with chemotherapy. Application of Hyperthermia in the Treatment of Cancer edited by R. D. Issels and W. Wilmanns, pp. 200-204. J. F., 1985, Chemical modifiers of radiosensitivity-theory and reality: a review. InterFOWLER, national Journal of Radiation Oncology, Biology and Physics, 11, 665-674. FRANK, A. J., 1986, Misonidazole and other hypoxia markers. Metabolism and applications. International Journal of Radiation Oncology, Biology and Physica, 12, 1195-1202. C. F., ANDERSON, R. M., HUTTER,J. J., BLITT,C. D., MALONE,J. HERMAN, T. S. ZUKOSKI, M., LARSON,D. F., DEAN,J. C. and ROTH,H. B., 1982, Whole-body hyperthermia and chemotherapy for treatment of patients with advanced, refractory malignancies. Cancer Treatment Reports, 66, 259-265. K. N. S., KAUFMANN,M. E., LEE, J. B. and LEE, HERMAN, T. S., TEICHER,B. A., CATHCART, M., 1988a, Effect of hyperthermia on cis-diamminedichloroplatinum(ir) (rhodamine 123),[tetrachloroplatinum(11)] in a human squamous carcinoma cell line and a cisdiamminedichloroplatinum(I1)-resistant subline. Cancer Research, 48, 5 101-5 105. HERMAN, T. S., TEICHER, B. A . , CHAN,V., COLLINS,L. S., KAUFMANN, M. E. and LOH, C.,

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Whole-body hyperthermia as an adjuvant to treatment with platinum complexes with or without etanidazole in mice bearing the Lewis lung carcinoma or the FSaLL fibrosarcoma.

The response of s.c. primary and metastatic Lewis lung carcinoma to five antitumour platinum complexes with or without tolerable whole-body hypertherm...
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