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ORIGINAL ARTICLES |
From the Departments of Psychology and Biology, Trent University, Peterborough, Ontario, Canada (L.R.K.); the Department of Kinesiology, University College of the Fraser Valley (H.N.A., K.S.S.), Abbotsford, British Columbia, Canada; and the Department of Cellular & Physiological Sciences, Faculty of Medicine, University of British Columbia (J.T.E., J.W.), Vancouver, British Columbia, Canada.
Address correspondence and reprint requests to Leslie R. Kerr, PhD, Departments of Psychology and Biology, Trent University, 1600 West Bank Drive, Peterborough, Ontario, K9J 7B8 Canada. E-mail: lkerr{at}trentu.ca
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ABSTRACT |
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Methods: Mice were reared either individually (I) or in groups (G). At 2 to 4 months, mice were injected with tumor cells and retained in their original housing conditions or rehoused into different experimental groups (GG, IG, II, GI) either immediately (experiment 1) or 14 days later (experiment 2); chemotherapy was administered when tumors weighed approximately 0.8 g.
Results: In experiment 1, IG and GG mice had better responses to chemotherapy than GI mice. Chemotherapy increased CORT levels in II mice and decreased GH levels in GI mice compared with those of their drug vehicle-treated counterparts. Under the temporal conditions of experiment 2, IG and GG mice lost the advantage seen in experiment 1 in terms of tumor and host responses to chemotherapy. Before chemotherapy administration, CORT levels in IG mice and GH levels in GI mice were higher than those in mice in all other housing conditions. At 1 day after chemotherapy, CORT levels were higher for chemotherapy-treated than for drug vehicle-treated IG mice, and at 5 days post chemotherapy, GH levels were higher in GI than in IG mice.
Conclusions: Temporal relationships among tumor cell injection, rehousing, and chemotherapy administration critically influence responses to chemotherapy; these effects may be mediated, in part, by alterations in hormone levels.
Key Words: housing • chemotherapy • hormones • temporal interactions • Shionogi carcinoma
Abbreviations: GG = from group to group housing; II = from individual to individual housing; IG = from individual to group housing; GI = from group to individual housing; CORT = corticosterone; GH = growth hormone; T = testosterone; AD = Adriamycin; CY = cyclophosphamide; TGD = tumor growth delay; SC115 = Shionogi carcinoma 115; C = tumor cell-injected, chemotherapy-treated mice; V = tumor cell- injected, drug vehicle-treated mice.
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INTRODUCTION |
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We have developed an animal tumor model that uses the transplantable, androgen-responsive Shionogi mouse mammary carcinoma (SC115) to investigate the effects of social housing conditions on tumor growth rate and chemotherapeutic efficacy. Mice are reared individually then group housed (IG), reared in groups then individually housed (GI), or experience no change from their original rearing conditions (II or GG). Our previous studies demonstrate that tumor growth rate as well as both tumor and host responses to chemotherapy (Adriamycin [AD] and cyclophosphamide [CY]) are significantly influenced not only by experimental housing conditions, but also by the timing of the formation of housing conditions in relation to tumor cell injection or chemotherapy initiation (15,16). Specifically, when housing conditions are formed immediately after tumor cell injection, GI mice have significantly faster tumor growth rates than IG mice, and II and GG mice have intermediate (between GI and IG) tumor growth rates. If chemotherapy is then initiated when tumors are approximately 0.8 g in size (14–20 days after housing condition formation), IG mice have a better tumor response to chemotherapy (longer tumor growth delay [TGD]), a better host response to chemotherapy (lose less weight), and a greater overall survival probability compared with GI mice (15). In contrast, if after tumor cell injection, mice remain in their original rearing conditions (I or G) for 14 days, until tumors are approximately 0.8 g, and experimental housing conditions are formed at that time, II mice have significantly faster tumor growth rates than IG and GG mice, whereas GI mice have intermediate tumor growth rates (16). In this case, if chemotherapy is then initiated 1 day after experimental housing condition formation, GI mice have better tumor and host responses to chemotherapy compared to IG and II mice, yet no differences in survival probabilities are observed among experimental conditions (16).
We have also shown that social housing conditions differentially influence plasma hormone levels. When housing conditions are formed immediately after tumor cell injection, IG mice (slowest tumor growth rate) have elevated levels of CORT, whereas GI mice (fastest tumor growth rate) have elevated levels of testosterone (T) compared with mice in the other housing conditions (11,17). These changes are seen at 1 to 7 days but not 21 days after tumor cell injection and formation of social housing conditions. We also have preliminary data demonstrating that growth hormone (GH) levels at 3 days after tumor cell injection and formation of experimental housing conditions are significantly higher in GI compared with IG mice.
Hormones, including T, CORT, and GH, may differentially influence the cytotoxic effects of chemotherapeutic drugs on SC115 tumors. For example, after castration, SC115 tumor response to AD and CY is increased significantly by administering exogenous T at levels submaximal for tumor growth (18). The timing of hormone administration relative to chemotherapy initiation also can differentially influence tumor response to chemotherapy. For example, T administered before but not after CY treatment increases the cytotoxic effects of CY (19), whereas the antitumor effects of CY are decreased by an increase in CORT levels before CY administration (12,20). However, an increase in CORT levels may also have beneficial effects in terms of host response to chemotherapy by protecting the animal from the toxic side effects of cytotoxic drugs (21,22). Furthermore, although increased GH levels may increase tumor cell proliferation, including SC115 tumor proliferation (23), GH reduces chemotherapy-induced decreases in immune activity and body weight (24,25) and therefore may play a role in augmenting chemotherapeutic efficacy.
Because CORT, T, and GH levels are altered among mice in the different housing conditions in our animal tumor model, influence SC115 growth rate, and modulate metabolic pathways of the host, including enzymes responsible for drug metabolism (5,11,18,20,25), we hypothesized that changes in these hormones resulting from social housing conditions, tumor development, and/or chemotherapy may play a role in the differential responses to chemotherapy that we have observed. Thus, the present study asked if: a) plasma levels of CORT, GH, and/or T measured before (0 days) or 1 or 5 days after chemotherapy administration are differentially altered among mice in the different housing conditions and b) the temporal relationships between the formation of housing conditions and tumor cell injection and/or chemotherapy administration differentially affect CORT, GH, and T levels. The mechanisms by which psychosocial stressors such as social housing conditions influence chemotherapeutic efficacy are poorly understood and are likely the result of multiple factors, including hormones. The present study is among the few to investigate whether alterations in hormone levels are associated with the differential effects of social conditions on chemotherapeutic efficacy.
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MATERIALS AND METHODS |
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Experimental Animals
The DD/S mouse colony was bred and maintained in-house.
Experiment 1
After weaning, male mice (n = 136) were housed in rodents cages (18 x 29 x 13 cm) either individually (I) or in groups of three (G) (Fig. 1). At 2 to 4 months of age, mice in each housing condition were injected subcutaneously with 2 x 106 tumor cells and immediately rehoused or maintained in their original housing conditions according to our published protocol (17): a) II mice raised individually remained individually housed; b) IG mice raised individually were rehoused in groups of 5; c) GG mice raised in groups of 3 remained in their rearing groups; and d) GI mice raised in groups of 3 were separated and rehoused individually. Mice within each housing condition were randomly assigned into tumor cell injection groups receiving either chemotherapy (C; n’s per group = 10 II, 18 IG, 13 GG, 12 GI) or drug vehicle (V; n’s per group = 15 II, 27 IG, 23 GG, 18 GI; Fig. 1). One day after tumor cell injection and formation of experimental housing conditions, all mice were exposed to an acute stressor for 15 minutes per day, 5 days per week to one of five different novel environments, a treatment that enhances differences in tumor growth rate among mice in the experimental housing conditions and increases plasma corticosterone levels compared with nonstressed mice but does not differentially alter plasma corticosterone among mice in the different social housing conditions (17). Eleven days after tumor cell injection, mice were weighed and caliper measurements of the tumors were taken everyday. Once tumor weights reached 0.8 ± 0.2 g, chemotherapy/drug vehicle treatment was initiated, and body and tumor weights were measured every second day. Tumor weights were calculated according to the formula (27):
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Tumors reached 0.8 ± 0.2 g at approximately 17 days for II mice, 22 days for IG mice, 16 days for GG mice, and 15 days for GI mice. Body and tumor weights were not measured on the termination day when trunk blood was collected for hormone analyses so that basal hormone levels could be measured.
Experiment 2
Like in experiment 1, after weaning, male DD/S mice (n = 130) were housed individually (I) or in groups (G) (Fig. 1) and at 2 to 4 months of age were injected subcutaneously with tumor cells. In contrast to experiment 1, mice remained in their original housing conditions (I or G) after tumor cell injection. Under these conditions, tumor growth rate and hormone levels are similar in both I and G housing conditions (11,15). Beginning 11 days after tumor cell injection, mice were weighed and caliper measurements of the tumors were taken daily until the mean tumor weight reached 0.8 ± 0.2 g (which occurred approximately 14 days after tumor cell injection). At this time, experimental housing conditions were formed and tumor and/or body weights were measured every second day (as described in experiment 1). Mice in each experimental housing condition were randomly assigned into tumor cell injection groups receiving either chemotherapy (n’s per group = 10 II, 20 IG, 11 GG, 11 GI) or drug vehicle (n’s per group = 15 II, 29 IG, 17 GG, 17 GI; Fig. 1), and treatment and exposure to acute novelty stress began on the day after the formation of experimental housing conditions.
Chemotherapy
In both experiments, chemotherapy or drug vehicle (0.9% NaCl) treatment began on the day after the mean tumor weight of mice within a housing condition reached 0.8 ± 0.2 g (Fig. 1). Chemotherapy consisted of a combination of AD (Adria Laboratories of Canada Ltd., Mississauga, ON, Canada) at 4.0 mg/kg and CY (Procytox; Horner, Montreal, PQ, Canada) at 61.5 mg/kg administered intraperitoneally at 3:00 PM to 5:00 PM (8–10 hours after lights on). The doses of drugs used have been shown to be optimal for SC115 tumor regression with minimal toxic effects (15,18). Mice were monitored daily for drug toxicity assessed by morbidity and mortality.
Plasma Hormone Levels
In both experiments, animals were killed at 8:00 AM to 11:30 AM either before (0 days) or 1 or 5 days after chemotherapy/drug vehicle administration. Mice were not exposed to novelty stress on the termination day so that basal hormone levels could be measured. Trunk blood was collected in heparinized tubes, centrifuged at 2200 g for 10 minutes at 4°C, and plasma was stored at –70°C until assayed. Note that for those mice killed on 0 days, blood was collected before administration of chemotherapy or drug vehicle treatment. Thus, to reduce the number of experimental animals used, only one subset of mice from each housing condition was killed on 0 days and served as the respective comparison groups for both chemotherapy and drug vehicle-treated mice 1 and 5 days posttreatment.
Corticosterone levels were measured by radioimmunoassay (RIA) as described previously (17,28). Briefly, 33.3 µL of plasma was extracted in 300 µL of absolute ethanol. After incubation with dextran-coated charcoal (Fisher Scientific Ltd., Vancouver, BC, Canada) to absorb and precipitate free CORT, 100 µL each of antiserum (ICN Biomedicals Inc., Costa Mesa, CA) and tritiated tracer (New England Nuclear, Guelph, ON, Canada) were added to all samples. After an overnight incubation, all samples were quantified with liquid scintillation counting (Scintisafe Econo2 Sx21–5; Fisher Scientific Ltd.).
Growth hormone levels were measured by RIA using purified mouse serum GH RIA immunoreagents distributed by the U.S. National Institute of Diabetes and Digestive and Kidney Diseases’ National Hormone and Pituitary Program (Harbor-UCLA Medical Center Research and Education Institute, Torrance, CA).
Testosterone levels were measured with an RIA kit (ImmuChem; ICN Biomedicals Inc.). Samples were counted in Scintisafe Econo2 Sx21 to 5 (Fisher Scientific Ltd.).
For all RIAs, the interassay and intraassay variabilities were less than 10%.
Statistical Analyses
Tumor response to chemotherapy was measured as the difference in tumor weights between drug vehicle-treated and chemotherapy-treated mice within corresponding housing conditions; tumor weights for mice in all housing conditions in drug vehicle- and chemotherapy-treated groups were rank-ordered and paired accordingly. Thus, tumor response to chemotherapy (g) = [tumor weight 4 days after drug vehicle administration minus tumor weight 4 days after chemotherapy administration]. Positive values indicate tumor response to chemotherapy; the greater the difference, the better the tumor response. Host response to chemotherapy was measured by the percentage of body weight lost, where percent body weight loss = [body weight 4 days after chemotherapy/drug vehicle administration minus body weight on the day of chemotherapy/drug vehicle injection]/[body weight on the day of chemotherapy/drug vehicle injection] x 100, where body weight = [gross body weight minus tumor weight]. Negative values indicate weight loss. Tumor growth rates, tumor response to chemotherapy, and body weight loss were analyzed by analyses of variance (ANOVAs) for the factors of group, days, and treatment, when applicable. To examine changes in hormone levels over days, separate two-way ANOVAs for the factors of group (II, IG, GG, GI) and day (0, 1, and 5 days) were run for chemotherapy-treated and drug vehicle-treated conditions. To determine the effect of chemotherapy relative to drug vehicle treatment at 1 and 5 days after injection, three-way ANOVAs for the factors of group, day, and treatment were run. For tumor growth rate and hormone analyses, days was treated as a repeated-measures variable. Significant main effects or interactions were analyzed by Tukey’s post hoc tests. Analyses of tumor response to chemotherapy and body weight loss were performed on the subset of mice that were alive up to 5 days after chemotherapy/drug vehicle administration.
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RESULTS |
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Tumor response to chemotherapy (tumor growth delay; the difference in tumor weights between drug vehicle-treated and chemotherapy-treated mice within corresponding housing conditions) was consistent with and extended our previous data (15). Analysis of the main effect of group (F (3,22) = 3.589, p < .05) revealed that tumor response to chemotherapy was significantly greater in IG and GG mice than in GI mice (p values <.05; Table 1). Tumor response to chemotherapy for II mice was intermediate and not significantly different from that of mice in the other housing conditions.
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Host response to chemotherapy (body weight loss) revealed a significant effect of group (F (3,22) = 4.35, p = .01). Similar to our previous data (15), GI mice lost significantly more weight than GG mice (p = .01) and marginally more weight than IG mice (p = .061; Table 2). There was also a significant effect of group (F (3,20) = 6.15, p < .01) for tumor-bearing, drug vehicle-treated mice; GI mice lost significantly more weight than IG mice (p < .01; Table 2). Weight loss was similar among drug vehicle- and chemotherapy-treated mice.
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Plasma Hormone Levels
Corticosterone
CORT levels did not differ significantly among mice in the different housing conditions before (0 days) or after (1 day or 5 days) either vehicle or chemotherapy administration. Examination of the effect of chemotherapy relative to drug vehicle treatment revealed a significant treatment x group x day interaction (F (3,84) = 3.690, p < .05). Post hoc analysis indicated that CORT levels at 1 day after vehicle/chemotherapy administration were significantly higher for II mice receiving chemotherapy than for their drug vehicle-treated counterparts (C-II > V-II, p < .05; Fig. 3).
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Growth Hormone
GH levels did not differ significantly among mice in the different housing conditions before either vehicle or chemotherapy administration (0 days). However, examination of GH levels after treatment revealed a significant group x day interaction for drug vehicle-treated mice (F (6,51) = 4.107, p < .01) and a significant main effect for day for chemotherapy-treated mice (F (2,58) = 5.701, p < .01; Figure 3). Post hoc analysis indicated that at 1 day after drug vehicle administration, GH levels increased significantly in GI mice and also were higher than those in vehicle-treated mice in all other housing conditions (p values <.05; Fig. 3). For chemotherapy-treated mice, no differences in GH levels among housing conditions were observed, although GH levels were higher at 1 day than at 0 days (p < .01). Examination of the significant treatment x group interaction (F (3,71) = 7.811, p < .001) revealed that overall (regardless of day), GH levels were significantly lower for C-GI than for V-GI mice (p < .01; Fig. 3). This difference appears to be mainly the result of the significant increase in GH levels in V-GI mice at 1 day, which did not occur in C-GI mice.
Testosterone
T levels did not differ significantly among mice in the different housing conditions before either vehicle or chemotherapy administration (0 days). Examination of T levels after drug vehicle administration revealed a significant group x day interaction (F (6,66) = 3.261, p < .001). Significant increases in T levels were seen in GG mice at 5 days after vehicle injection, and levels were higher than those in drug vehicle-treated IG and GI mice (p values <.05; Fig. 3). T levels did not differ significantly in mice in the chemotherapy treatment group or between chemotherapy and drug vehicle-treated mice.
Experiment 2
For mice in the drug vehicle condition, tumor growth rates were similar in I- and G-housed mice before the formation of experimental housing conditions (Fig. 4). After housing condition formation, a significant group x day interaction (F (6,18) = 4.989, p < .01) was observed. Tumor growth rates at 18 days after tumor cell injection (4 days after formation of experimental housing conditions) were significantly faster in GI than in II and IG mice (p values <.01) and faster in GG than in IG mice (p < .05; Fig. 4).
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Tumor response to chemotherapy, measured at 4 days after chemotherapy administration (18 days after tumor cell injection and 5 days after formation of experimental housing conditions), was not significantly different among mice in the different housing conditions (Table 1).
Analysis of host response to chemotherapy (body weight loss) revealed a marginal effect of group (F (3,21) = 2.73, p = .070). Consistent with our previous study (16), IG mice lost marginally more weight than GI mice (p = .072; Table 2). There were no significant differences in weight loss for II and GG mice. For drug vehicle-treated mice, no significant differences in body weight loss among mice in the different housing conditions were observed. Overall, body weight loss was marginally greater for chemotherapy- than for drug vehicle-treated mice (TRT; F (1,40) = 3.843, p = .057; Table 2).
Plasma Hormone Levels
Corticosterone
Analysis of the significant main effect of group (F (3,21) = 7.989, p < .001) revealed that before either drug vehicle or chemotherapy administration (0 days), CORT levels in IG mice were significantly higher than those in all other housing conditions (p’s < .05; Fig. 5). Examination of CORT levels after either drug vehicle or chemotherapy administration revealed significant group x day interactions for both drug vehicle- (F (6,60) = 6.765, p < .001) and chemotherapy- (F (6,62) = 3.713, p < .01) treated mice. These interactions appear to be mainly the result of the significantly elevated CORT levels seen in IG mice at 0 days and the significant decrease in CORT that occurred after both vehicle and chemotherapy administration. That is, CORT levels were higher in V-IG mice at 0 days than at both 1 day and 5 days (p values <.01), whereas CORT levels were higher in C-IG mice at 0 days than at 5 days (p < .05; Fig. 5). Accordingly, comparison of drug vehicle- and chemotherapy-treated mice revealed a significant treatment x group x day interaction (F (3,80) = 3.671, p < .05), where at 1 day, C-IG had higher CORT levels than V-IG mice (p < .01; Fig. 5).
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Growth Hormone
Before either drug vehicle or chemotherapy administration (0 days), GH levels in GI mice were significantly higher than those in all other housing conditions (p values <.01), and GH levels in II mice were significantly higher than those for IG mice (p < .05). Examination of GH levels after drug vehicle/chemotherapy administration revealed a significant group x day interaction for both drug vehicle- (F (6,51) = 9.440, p < .001) and chemotherapy- (F (6,54) = 7.240, p < .001) treated mice. These interactions are attributed primarily to the significantly elevated GH levels in GI mice at 0 days. That is, for both drug vehicle- and chemotherapy-treated mice, GH levels in GI mice were significantly higher before injection (0 days) than after injection (1 day and 5 days; p values <.05; Fig. 5). C-GI mice also had higher GH levels at 5 days than C-IG mice (p < .05). Examination of the effect of chemotherapy relative to drug vehicle treatment revealed a significant treatment x group x day interaction (F (3,71) = 4.591, p < .01). At 5 days, GH levels were higher for C-GI than for V-GI mice (p < .05; Fig. 5).
Testosterone
Before either drug vehicle or chemotherapy administration (0 days), T levels did not significantly differ among housing conditions or between treatment conditions. After drug vehicle administration, a significant main effect of group (F (3,52) = 3.954, p = .01) was observed. T levels were significantly higher in V-GI than in V-II mice (p = .01) and marginally higher in V-GI than in V-IG and V-GG mice (p = .060 and p = .086, respectively; Fig. 5). T levels did not differ significantly among housing conditions for chemotherapy-treated mice or between chemotherapy- and drug vehicle-treated mice.
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DISCUSSION |
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It is remarkable that a psychosocial variable such as housing condition can still profoundly influence tumor growth rate even if tumors are large (0.8 g) when social housing conditions are formed, like in experiment 2. The present data support our previous work (16,17) in demonstrating that tumor growth rates are slowest in mice in the IG condition regardless of the temporal relationship between tumor cell injection and formation of housing conditions. These findings suggest that the physiological changes (including hormone levels) within mice of the IG housing condition confer some advantage over those in all other conditions. The present data also extend our previous work in which we demonstrated a relationship of CORT and T, respectively, with tumor growth rates in IG and GI mice at 1 to 7 days after tumor cell injection and formation of housing conditions at a time when tumor size was negligible (11). Notably in experiment 2, we show that alterations in hormone levels 1 to 6 days after formation of housing conditions and 14 days after tumor cell injection, when tumor size is large (0.8 g), also may be related to the differential tumor growth rates among housing conditions. That is, at 1 day after housing condition formation (0 days of vehicle/chemotherapy administration), CORT levels in IG mice (slowest growing tumors) and GH levels in GI mice (fastest growing tumors) were higher than those in all other experimental housing conditions. However, the temporal conditions of this experiment appear to increase the variability in tumor growth rate, because tumor growth rates only partially replicate those of a previous study using the same temporal conditions (16). Variability in the influence of housing conditions on tumor growth rate may be expected because the capacity of physiological factors such as hormones to differentially influence tumor growth among housing conditions may be altered by the microenvironment of a large tumor. That is, because tumor size was large at the time of the formation of experimental housing conditions in experiment 2, tumor-related factors may be influencing the differential tumor growth rates observed (29) and could vary somewhat between experiments.
Despite this variability in tumor growth rates, tumor and host responses to chemotherapy in the present experiments are comparable to those of our previous studies (15,16). Under the temporal relationships of experiment 2, IG and GG mice lost the advantage over GI mice seen in experiment 1 in terms of tumor and host responses to chemotherapy. Indeed, in experiment 2, there were no differences among housing conditions in tumor response to chemotherapy, and IG mice now lost marginally more weight than GI mice, despite having a slower tumor growth rate. These data, like those of our previous study (16), suggest that tumor growth rates do not play a role in mediating the differential effects of social housing conditions on tumor and host responses to chemotherapy.
Although the mechanisms by which psychosocial factors, including social conditions, regulate chemotherapeutic efficacy are poorly understood, there is some evidence that alterations in circulating hormone levels (including CORT, GH, and/or T) (12,18,20) with or without immune system involvement (13,19,24,25,30) may influence the effectiveness of chemotherapy treatment. A major goal of the present study was to determine if the temporal relationships among tumor cell injection, formation of experimental housing conditions, and chemotherapy administration differentially affect CORT, T, and GH levels and whether changes in these hormones are related to the differential tumor and host responses to chemotherapy observed. Previously, we have shown that plasma levels of CORT, GH, and T are differentially altered in mice among housing conditions at 1 to 7 days, but not at 21 days, after tumor cell injection and formation of housing conditions (11,17). We have also demonstrated that aggressive, defensive, and sleeping behaviors are differentially influenced by social housing conditions within the first 2 days after tumor cell injection and formation of housing conditions, but after this time, no significant differences in behavioral activity are observed among groups (31). In experiment 1, hormone levels were measured and chemotherapy was administered 17 to 23 days after tumor cell injection and formation of housing conditions. Thus, at the time of chemotherapy administration in the present experiment, mice have adapted to their social housing conditions as evidenced by similar hormone levels as well as aggressive, defensive, and sleeping behaviors (11,17,31). Here, we demonstrate that although tumor and host responses to chemotherapy were better in IG and GG mice than in GI mice, CORT, GH, and T levels were similar among mice in the different housing conditions before and after chemotherapy administration. Although hormone levels were similar among all chemotherapy-treated mice, the established social dynamics (including grooming, fighting, and group sleeping (31) of mice in the IG and GG housing conditions at the time of chemotherapy administration may still confer an advantage over mice in the II and GI conditions, thus increasing chemotherapeutic efficacy (5,13,18,32). One alternative mechanism mediating the differential effects of social housing conditions on tumor and host responses to chemotherapy may be through differential immune activation (33) because we have shown previously that the SC115 tumor differentially stimulates natural killer cell (NK) cell activity in mice in the GI and IG conditions (34). Whether the greater chemotherapeutic efficacy observed in IG and GG mice was the result of an increased immunoreactivity toward the tumor compared with those in GI and II mice remains to be examined. Overall, under the temporal conditions of experiment 1, we demonstrated that chemotherapy significantly increased CORT levels in II mice and decreased GH levels in GI mice compared with those of their drug vehicle-treated counterparts, but tumor and host responses to chemotherapy do not appear to be related to alterations in CORT, T, or GH levels, at least at the time points examined.
In contrast to experiment 1, it appears that under the temporal conditions of experiment 2, alterations in hormone levels may play some role in mediating the responses to chemotherapy among mice in the different housing conditions. In experiment 2, hormone levels were measured and chemotherapy was administered 1 to 6 days after formation of housing conditions. In the present study, tumor and host responses to chemotherapy were not significantly different in mice among the experimental housing conditions, although IG mice did lose moderately more weight than GI mice. However, under the same experimental conditions, we previously demonstrated that if responses to chemotherapy are measured up to 70 days after the first injection of chemotherapy (compared with 4 days in the present study), tumor and host responses to chemotherapy are better in GI mice than in IG mice (16). Thus, in the present experiment, it may be too early after chemotherapy administration to observe significant differences in tumor and host responses to chemotherapy.
Examination of plasma hormone levels in chemotherapy-treated mice in experiment 2 revealed that before chemotherapy administration (0 days), CORT levels in IG mice and GH levels in GI mice were significantly higher than those in all other housing conditions, and, at 1 day after chemotherapy, both CORT and GH levels decreased from 0-day levels. However, CORT was still significantly higher in chemotherapy-treated than in drug vehicle-treated IG mice at 1 day, and GH was still significantly higher in chemotherapy-treated GI mice than in both drug vehicle-treated GI mice and chemotherapy-treated IG mice at 5 days. Because in experiment 2, chemotherapy was administered 1 day after the formation of social conditions, the increased fighting and defensive behaviors that occur at this time among IG mice (31) may play a role in decreasing tumor response to chemotherapy and increasing weight loss and toxic effects of chemotherapy (15,16). Although fighting may represent a form of coping response in established social groups (17,31), in newly formed male groups, stressors related to the establishment of social hierarchies (such as social defeat) have been shown to have marked physiological consequences, including increased CORT secretion and decreased GH secretion and immune function (10,11,16). Thus, increased levels of CORT (as seen in IG mice in the present study) may suppress the antitumor activity of CY through acceleration of drug metabolism or suppression of immune function and if prolonged, elevated CORT levels may further decrease immune activity and increase toxic side effects (12–14,20,22), whereas increased levels of GH (as seen in GI mice) may reduce the immunosuppressive effects of chemotherapy and other toxic side effects such as weight loss (24,35,36). The specific roles that CORT and GH may play in mediating the differential effects of social housing condition on chemotherapeutic efficacy remain to be determined. Future studies examining immune and/or tumor-specific factors as well as active drug-to-metabolite ratios may elucidate further the mechanisms that are involved in the differential effects of social conditions on chemotherapeutic efficacy.
Several factors, acting either independently or in an interactive fashion, may play a role in mediating stressor-induced alterations in chemotherapeutic efficacy (2,5,21,37). Together, the data of experiments 1 and 2 demonstrate that the influence of social condition on chemotherapeutic efficacy in our model is independent of tumor growth rate and that altering the temporal relationships among tumor cell injection, formation of experimental housing conditions, and chemotherapy administration differentially affects CORT and GH levels as well as tumor and host responses to chemotherapy. It is unlikely, however, that hormonal alterations among mice in the different housing conditions are the only factors involved. Overall, the present studies illustrate the complexity of the factors, including the temporal relationships among tumor cell injection, formation of social housing conditions, and chemotherapy administration that may significantly influence tumor growth as well as tumor and host responses to chemotherapy.
We thank Darcy Wilkinson and Glenn Edin for their expert technical assistance. We also thank Dr. A.F. Parlow from the U.S. National Hormone and Pituitary Program, Harbor-UCLA Medical Center Research and Education Institute, for carrying out the growth hormone RIA.
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This research was supported by grant CA73446 from the National Cancer Institute, National Institutes of Health. L. R. Kerr was supported by the Roman M. Babicki Scholarship for Cancer Research.
DOI:10.1097/01.psy.0000244024.35209.d4
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). (A) Corticosterone (CORT): CORT levels were significantly higher at 1 day for C-II than for V-II mice (p < .05; •). (B) Growth hormone (GH): before vehicle/chemotherapy injection (0 days), GH levels did not differ significantly among mice in the housing conditions. At 1 day after drug vehicle injection, GH levels were higher in GI mice compared with all other housing conditions (p values <.05; *). Also, GH levels in GI mice were significantly higher at 1 and 5 days than at 0 days (p values <.05; 
