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Psychosomatic Medicine 63:973-984 (2001)
© 2001 American Psychosomatic Society

ORIGINAL ARTICLE

Effects of Social Housing Condition on Chemotherapeutic Efficacy in a Shionogi Carcinoma (SC115) Mouse Tumor Model: Influences of Temporal Factors, Tumor Size, and Tumor Growth Rate

Leslie R. Kerr, PhD, Rajinder Hundal, BSc, W. André Silva, MD, Joanne T. Emerman, PhD and Joanne Weinberg, PhD

From the Department of Anatomy, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

Address reprint requests to: Joanne Weinberg, PhD, Department of Anatomy, Faculty of Medicine, University of British Columbia, 2177 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada. Email: joannew{at}interchange.ubc.ca


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: The objective of this study was to investigate 1) whether social housing condition, tumor size, and tumor growth rate alter responses to chemotherapy and 2) whether the timing of tumor cell injection or chemotherapy initiation (relative to housing condition formation) influences tumor growth rate or the efficacy of chemotherapy.

METHODS: Mice were reared individually (I) or in groups (G). In experiment 1, mice were rehoused (IG or GI) or left in group housing (GG) immediately after tumor cell injection. In experiment 2, housing conditions (II, IG, GG, or GI) were formed when tumors weighed 1 g. Chemotherapy (adriamycin 4 mg/kg and cyclophosphamide 61.5 mg/kg IP) and exposure to acute novelty stress (15 min/d, 5 d/wk) were initiated 1 day after housing condition formation.

RESULTS: If chemotherapy was initiated when the tumor burden was undetectable (experiment 1), housing condition did not alter tumor response to chemotherapy, although IG mice lost the most weight and overall had the lowest probability of survival. If chemotherapy was initiated when tumors weighed 1 g (experiment 2), both tumor and host responses to chemotherapy were poorest for IG mice. Timing of tumor cell injection relative to housing condition formation also differentially influenced the rate of tumor growth in mice treated with the drug vehicle; in experiment 1, tumor growth rate was faster in GI and GG mice than in IG mice, whereas in experiment 2, the rate of tumor growth was faster in II mice than in GG and IG mice.

CONCLUSIONS: Altering the temporal relationships among social housing condition formation, tumor cell injection, and chemotherapy initiation differentially influences the rate of tumor growth and the efficacy of chemotherapy. Effects of housing condition are independent of tumor growth rate at chemotherapy initiation and, in terms of host responses, independent of tumor burden.

Key Words: Shionogi carcinoma, • psychosocial stress, • chemotherapy, • tumor and host responses, • survival probability.

Abbreviations: DMEM = Dulbecco’s modified Eagle’s medium;; GG = from group to group housing;; GI = from group to individual housing;; IG = from individual to group housing;; II = from individual to individual housing;; NTC = non–tumor cell–injected (tumor cell vehicle–injected), chemotherapy-treated mice;; SC115 = Shionogi carcinoma;; TC = tumor cell–injected, chemotherapy-treated mice;; TV = tumor cell–injected, drug vehicle–treated mice.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
In humans, stressful life events, the frequency of such events, and the ability to cope with stress have been shown to play a role not only in increased cancer risk and metastasis (1–7) but also in response to chemotherapy, including survival probability (6, 8), time to cancer reoccurrence after chemotherapy (5), and the variable incidences of the toxic effects of chemotherapy (9–13). However, a number of studies have reported little or no support for the association among stressful life events, coping, and cancer progression or chemotherapeutic efficacy (14–18). The complex relationships between psychosocial stressors and the progression of cancer or chemotherapeutic efficacy are difficult to investigate in humans because a number of issues may affect interpretation of the data. For example, the stage of treatment in which the patients are examined (3, 19, 20) as well as the form of psychosocial assessments used (3, 21, 22) may alter the association among psychosocial stressors, coping resources or strategies, and cancer treatment. In addition, timing of a stressful event relative to the initiation of treatment as well as tumor and host factors may affect interpretation of the data (9, 23–27).

Animal models allow investigation of the relationship among stressors, coping mechanisms, tumor growth, and responses to chemotherapy under more controlled conditions. However, even in animal models the data are complex. Factors such as the type of tumor; timing, duration, and severity of the stressor; the species, strain, or gender of the animal; and the ability to cope with the stressor have been shown to influence stress effects on tumor growth or chemotherapeutic efficacy (28–34). In animals, psychosocial stressors such as housing condition and psychological stressors such as forced restraint and rotation have been shown to affect tumor growth rates or metastasis of both transplantable and chemically induced tumors (35–40) as well as both tumor and host responses to chemotherapy (41–43).

We have developed an animal tumor model using the transplantable, androgen-responsive Shionogi mouse mammary carcinoma (SC115; Ref. 40). Our data demonstrate that a change in social housing condition as well as the direction of change (40, 44) can significantly influence tumor growth rate. Mice are reared either individually (I) or in groups (G) until 2 to 4 months of age, at which time tumor cells are injected and experimental housing conditions (IG or GI) are formed. Under these conditions tumor growth rate is reduced in IG mice and increased in GI mice compared with mice remaining in their original rearing conditions (II or GG; Refs. 40 and 44). Furthermore, subjecting mice to a daily acute novelty stress increases the difference in tumor growth rate between IG and GI mice (40).

In this same model we have also demonstrated that social housing condition can significantly influence both tumor response to chemotherapy (assessed by tumor growth delay) and the interaction between tumor and host responses to chemotherapy (assessed by overall survival probability). If chemotherapy is initiated when the mean tumor weight of mice in each housing condition reaches 1 g (approximately 14–18 days after tumor cell injection and social housing condition formation for GI and IG mice, respectively), tumor growth delay and overall survival probability are significantly greater in IG than in GI mice (41).

Earlier studies have shown that several factors may play a role in mediating stressor-induced alterations in chemotherapeutic efficacy, including tumor size and tumor growth rate as well as the timing of the stressful event relative to the initiation of treatment (25, 26, 45–49). Because in our initial study chemotherapy was initiated when tumors were growing at different rates (ie, slower in IG than in GI mice), although the tumors were of similar weights (1 g), the differential responses to chemotherapy may have been due to differences in social housing conditions, differences in tumor growth rate, tumor size at the time chemotherapy was initiated, or an interaction among these factors.

The present study was undertaken to begin to address these issues by examining 1) whether social housing condition, tumor size, or tumor growth rate at the time of chemotherapy initiation differentially influences tumor and host responses and 2) whether the timing of tumor cell injection or chemotherapy initiation (relative to when experimental housing conditions are formed) differentially influences tumor growth rate or chemotherapeutic efficacy.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Tumor Propagation and Experimental Animals
The androgen-responsive Shionogi mouse mammary carcinoma subline SC115 class A (50) was maintained by serial transplantation in male mice of the DD/S strain. Tumors weighing approximately 2 g were dissociated to single cells according to our standard protocol (40), and mice were injected subcutaneously in the interscapular region with 2 x 106 cells suspended in 0.1 ml of DMEM (Stem Cell Technologies Ltd., Vancouver, British Columbia, Canada).

Male DD/S mice between the ages of 2 and 4 months were the experimental subjects in experiment 1 (N = 113) and experiment 2 (N = 176).

Experiment 1: Effects of Social Housing Conditions and Tumor Size on Tumor and Host Responses to Chemotherapy
Mice were reared either individually or in groups. Immediately after injection of tumor cells (subcutaneous injection of 2 x 106 cells suspended in 0.1 ml of DMEM) or tumor cell vehicle alone (subcutaneous injection of 0.1 ml of DMEM), mice were either rehoused (from individual to group housing [IG] or from group to individual housing [GI]) or remained in their group housing condition (GG) according to our published protocol (40). Chemotherapy or drug vehicle was initiated 1 day later, when tumor burden was undetectable (similar to the adjuvant situation in humans). Mice within each housing condition were randomly assigned into tumor cell injection groups receiving either chemotherapy (TC: N = 20 IG, 14 GI, and 9 GG) or drug vehicle (TV: N = 10 IG, 8 GI, and 6 GG) or into tumor cell vehicle (no tumor cells) injection groups receiving chemotherapy (NTC: N = 20 IG, 15 GI, and 11 GG; Figure 1, A). The II housing condition was not used in this experiment because under the conditions of this study, tumor growth rate and hormone levels in II mice are similar to those in GG mice (40, 51). Beginning the day after rehousing and tumor cell or vehicle injection, all animals were exposed to an acute daily stressor; the stressor consisted of exposure to one of five different novel environments for 15 min/d, 5 d/wk, a treatment that we have shown enhances differences in tumor growth rate between experimental housing conditions (40). The five environments were 1) a clear plastic container, 9 cm in diameter x 7 cm in height; 2) a polypropylene container, 12 x 10 x 4 cm; 3) a cardboard box divided into compartments, 7 x 7 x 14 cm; 4) a polyethylene container, 6 cm in diameter x 10 cm in height; and 5) a standard rodent cage, 18 x 29 x 13 cm, empty of bedding, food, and water.



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  		Fig. 1. Experimental design of experiments 1 (A) and 2 (B).

 
Experiment 2: Effects of Social Housing Conditions and Tumor Growth Rate on Tumor and Host Responses to Chemotherapy
As in experiment 1, mice were reared either individually or in groups (Figure 1, B). To examine the influence of tumor growth rate on chemotherapeutic efficacy, experimental variables were manipulated such that chemotherapy was initiated when tumors weighed approximately 1 g (as in our initial study; Ref. 41) but were growing at similar rates. To accomplish this, tumor cells (2 x 106 cells suspended in 0.1 ml of DMEM) were injected subcutaneously, but mice remained in their original rearing condition (I or G) until mean tumor weights reached 0.8 ± 0.2 g, which occurred approximately 14 days after tumor cell injection. At that time mice were rehoused (IG or GI) or remained in their original rearing condition (II or GG), and chemotherapy or drug vehicle was initiated 1 day later (Figure 1, B). Tumor cell–injected mice in each of the experimental housing conditions (II, IG, GG, and GI) were randomly assigned to receive either chemotherapy (TC: N = 9 II, 23 IG, 13 GG, and 16 GI) or drug vehicle alone (TV: N = 12 II, 19 IG, 12 GG, and 14 GI). Mice within each housing condition that were injected with tumor cell vehicle (but no tumor cells) also received chemotherapy to assess the possible toxic side effects of chemotherapy independent of the presence of a tumor (NTC: N = 12 II, 20 IG, 15 GG, and 11 GI; Figure 1, B). As in experiment 1, mice were exposed daily to an acute novelty stress beginning the day after rehousing. Note that in both experiments 1 and 2, the stressor was initiated concurrently with chemotherapy. However, in experiment 1, this occurred 1 day after tumor cell injection, whereas in experiment 2, this occurred 14 days after tumor cell injection.

Body and Tumor Weight Measurements
In both experiments body weights were measured and mice were palpated every second day. Once the tumors were measurable (approximately 8–10 days after tumor cell injection), caliper measurements were taken every second day and tumor weights were calculated according to the following formula (tumor weight measured in grams; length and width measured in centimeters) (52): Go


Chemotherapy
Chemotherapy consisted of a combination of adriamycin (4.0 mg/kg; Adria Laboratories of Canada Ltd., Mississauga, Ontario, Canada) and cyclophosphamide (61.5 mg/kg; Procytox, Horner, Montreal, Quebec, Canada) in NaCl solution (drug vehicle). Drugs were administered intraperitoneally every 7 days for a total of three injection rounds. The doses of drugs selected for this study have been shown to be optimal for SC115 tumor regression with minimal toxic side effects (53). Mice were monitored every second day for drug toxicity (as assessed by morbidity, ie, body weight loss) and daily for mortality (survival probability).

Statistical Analyses
Tumor response to chemotherapy was analyzed using tumor growth delay, defined as the mean time for tumors in chemotherapy-treated mice to reach a specific weight minus the mean time for tumors in drug vehicle–treated mice to reach the same weight. Host response to chemotherapy was analyzed by 1) the percentage of body weight loss over the course of chemotherapy and 2) overall survival probability. Percentage of body weight loss was calculated as follows: Body Weight Loss = [(C2 or C3 - C1) ÷ C1] x 100, where C1 = body weight on day of chemotherapy initiation; C2 = body weight on day of second round of chemotherapy; and C3 = body weight on day of third round of chemotherapy. Negative values indicate weight loss between chemotherapy rounds. Only the data for body weight loss from C1 to C3 is shown (Table 1). Overall survival probability was determined using Kaplan-Meier plots and Cox proportional hazards regression (54, 55). Death, regardless of cause, was considered an event (ie, mice were killed when tumor weight exceeded 3.5 g or mice were found dead, presumably as a result of the toxic side effects of chemotherapy). Mice that were still alive 70 days after the first round of chemotherapy were considered censored. Tumor growth rate in drug vehicle–treated mice, body weight loss, and tumor growth delay were analyzed by analyses of variance for the factors of group and days with days treated as a repeated-measures factor. Significant main or interaction effects were further analyzed by Tukey’s post hoc tests.


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  		Table 1. Percentage of Body Weight Loss (mean ± SE) in Mice Over the Course of Chemotherapy or Drug Vehicle Treatment in Experiments 1 and 2
 

   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Tumor Growth Rates, Body Weight Loss, and Survival Probability in TV Mice
Experiment 1.
Consistent with the data from our initial study, in which social housing conditions were also formed immediately after SC115 tumor cell injection (41), analysis of tumor growth rate in mice treated with the drug vehicle in the present study revealed a significant group-by-days interaction (F(8,72) = 24,209, p < .001; Figure 2, A). Tukey’s post hoc analysis indicated that on days 15 and 17 after tumor cell injection and formation of experimental housing conditions, tumor growth rates were significantly faster in both GI and GG mice than in IG mice (GI = GG > IG, p values < .001). Consequently, survival probability was also greater in IG mice than in both GI and GG mice (IG > GI = GG, {chi}2 = 12.42 and 20.18, respectively, p values < .001; Figure 3, A). Analysis of the percentage of body weight loss similarly revealed a significant group-by-days interaction (F(2,14) = 3.629, p = .05; Table 1), probably reflecting a somewhat greater initial weight loss in IG and GG mice than in GI mice. However, post hoc analyses failed to reach significance.



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  		Fig. 2. Tumor growth in drug vehicle–treated (TV) mice. Experimental housing conditions were formed (A) immediately after tumor cell injection (experiment 1) or (B) approximately 14 days after tumor cell injection (when tumors weighed approximately 1 g) (experiment 2); arrow represents formation of experimental housing conditions. Tumor weights (mean ± SE) at five measurement times for drug vehicle–treated mice in the three housing conditions of experiment 1 (N = 10 IG, 6 GG, and 8 GI) and the four housing conditions of experiment 2 (N = 12 II, 19 IG, 12 GG, and 14 GI). For experiment 1, tumor growth rates for both days 15 and 17 were significantly faster in both GI and GG mice compared with IG mice (p values < .001). For experiment 2, tumor growth rate by 19 days after tumor cell injection was significantly greater in II mice compared with GG (p < .01) and IG (p < .001) mice.

 


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  		Fig. 3. Survival probability in experiment 1 in (A) tumor cell–injected mice receiving chemotherapy (TC) or drug vehicle (TV) and (B) in tumor cell vehicle–injected mice receiving chemotherapy (NTC). Day 0 is the day of chemotherapy (adriamycin 4.0 mg/kg and cyclophosphamide 61.5 mg/kg) or drug vehicle initiation. The first symbol represents the time at which the first death occurred in each condition. (A) For TV mice, survival probability was significantly greater in IG mice than in both GI and GG mice ({chi}2 = 12.42 and 20.18, respectively, p values < .001). As expected, TC mice (N = 9 GG, 14 GI, and 20 IG) survived significantly longer than TV mice (N = 6 GG, 8 GI, and 10 IG; {chi}2 = 38.371, p < .001). (B) For NTC mice (N = 11 GG, 15 GI, and 20 IG), survival probability was significantly greater in GI mice than in IG mice ({chi}2 = 4.588, p < .05).

 
Experiment 2.
Tumor growth rates in drug vehicle–treated mice were similar for individually and group-housed mice from 0 days until approximately 14 days after tumor cell injection, when mean tumor weights of mice in both conditions reached approximately 1 g, at which time experimental housing conditions (II, IG, GG and GI) were formed (Figure 1, B). Analysis of tumor growth rates after the formation of experimental housing conditions revealed a significant group-by-days interaction (F(6,92) = 2.395, p < .05; Figure 2, B). Post hoc analysis indicated that when the temporal relationship between tumor cell injection and formation of experimental housing conditions is altered, compared with that of our original experimental paradigm, tumor growth rates among the different housing conditions are also altered. Specifically, 5 days after formation of experimental housing conditions (approximately 19 days after tumor cell injection), tumor growth rates were significantly faster in II mice than in both IG and GG mice (II > IG = GG, p values < .01; Figure 2, B). GI mice had intermediate tumor growth rates that did not differ significantly from those of mice in the other experimental housing conditions. In addition, II mice had a marginally reduced survival probability compared with IG mice (II < IG, {chi}2 = 3.243, p = .072; Figure 4, A). For body weight loss, the significant main effect of group (F(3,48) = 4.207, p = .01) indicated that both II and IG mice lost significantly more weight than GG mice (II = IG > GG, p values < .05; Table 1), suggesting that body weight loss did not relate to tumor growth rate. Weight loss for GI mice did not differ significantly from that of mice in any other housing condition (Table 1).



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  		Fig. 4. Survival probability in experiment 2 in (A) tumor-bearing mice receiving either chemotherapy (TC) or drug vehicle (TV) and (B) tumor cell vehicle–injected mice receiving chemotherapy (NTC). Day 0 is the day of chemotherapy (adriamycin 4.0 mg/kg and cyclophosphamide 61.5 mg/kg) or drug vehicle initiation. The first symbol represents the time at which the first death occurred in each housing condition. (A) For TV mice, survival probability was marginally greater in IG than in II mice ({chi}2 = 3.243, p = .072). As expected, TC mice (N = 9 II, 23 IG, 13 GG, and 16 GI) had significantly greater overall survival probability than TV mice (N = 12 II, 19 IG, 12 GG, and 14 GI; {chi}2 = 57.778, p < .001). (B) For NTC mice (N = 12 II, 20 IG, 15 GG, and 11 GI), survival probability was significantly greater in II and GG mice than in IG mice ({chi}2 = 7.626, p < .01 and {chi}2 = 5.752, p < .05, respectively) and marginally greater in GI than in IG mice ({chi}2 = 2.812, p = .094). Survival probability was significantly higher in NTC than in TC mice ({chi}2 = 32.561, p < .001).

 
Tumor Response to Chemotherapy, Body Weight Loss, and Survival Probability in TC Mice
Experiment 1.
Tumor response to chemotherapy was similar among mice in all experimental housing conditions. That is, no tumors were palpable in any mice for up to 70 days after chemotherapy initiation, suggesting that chemotherapy initiated 1 day after tumor cell injection is equally effective in containing tumor growth in all mice regardless of housing condition. Similarly, no significant differences in overall survival probability were observed among mice in the different experimental housing conditions (Figure 3, A). However, host response to chemotherapy, assessed by body weight loss over the course of chemotherapy, revealed significant effects of both group (F(2,32) = 10.760, p < .001) and days (F(2,32) = 312.936, p < .001). Both GI and GG mice lost significantly less weight than IG mice (GI = GG < IG, p values < .01; Table 1).

As expected, survival probability for chemotherapy-treated mice was significantly greater than that for drug vehicle–treated mice (TC > TV, {chi}2 = 38.371, p < .001; Figure 3, A), and mice treated with chemotherapy lost significantly more weight than those receiving drug vehicle (TC > TV, p < .001; Table 1). In addition, for all mice treated with chemotherapy, tumor cell–injected mice lost significantly more weight than tumor cell vehicle–injected mice regardless of experimental housing condition (TC > NTC, p values < .05; Table 1). Interestingly, however, no significant differences in survival probabilities were observed between tumor cell–injected and tumor cell vehicle–injected mice receiving chemotherapy (Figure 3, A and B).

Experiment 2.
Social housing condition significantly affected both tumor and host responses to chemotherapy. Analysis of tumor responses, measured by tumor growth delay, revealed a significant effect of group (F(3,159) = 3.624, p = .01); GI mice had a significantly longer delay in tumor growth than II mice (GI > II, p < .01) and a marginally longer delay than IG mice (p = .098; Table 2). Similarly, analysis of host response to chemotherapy, measured by the percentage of body weight loss over the course of chemotherapy treatment, revealed a significant main effect of group (F(3,35) = 4.170, p = .01); GI mice lost significantly less weight than IG mice (GI < IG, p < .05; Table 1) and marginally less weight than II mice (p = .07; Table 1). However, social housing condition did not influence the overall survival probabilities among tumor cell–injected, chemotherapy-treated mice. For GG mice, both tumor growth delay and percentage of body weight change did not differ significantly from those of mice within the other social housing conditions.


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  		Table 2. Tumor Growth Delaya (mean ± SE) in Chemotherapy-Treated Mice in Experiment 2
 
Once again, as expected, overall survival probability was greater for chemotherapy-treated mice than for drug vehicle–treated mice (TC > TV, {chi}2 = 57.778, p < .001; Figure 4, A), and mice treated with chemotherapy lost significantly more weight than those receiving drug vehicle (TC > TV, p < .001; Table 1). In addition, survival probability was significantly greater for tumor cell vehicle–injected than for tumor cell–injected, chemotherapy-treated mice (NTC > TC, {chi}2 = 32.561, p < .001; Figure 4, A and B). However, no significant differences in body weight loss were observed between tumor cell–injected and tumor cell vehicle–injected mice receiving chemotherapy.

Effects of Social Housing Condition on Body Weight Loss and Survival Probability in NTC Mice
Experiment 1.
For tumor cell vehicle–injected, chemotherapy-treated mice, survival probability was significantly less for IG than for GI mice (IG < GI, {chi}2 = 4.588, p < .05; Figure 3, B); survival probability for GG mice did not differ significantly from that of IG and GI mice. Analysis of body weight loss over the course of chemotherapy revealed a significant group-by-days interaction (F(2,43) = 4.332, p < .05). Similar to the results in their tumor cell–injected counterparts, tumor cell vehicle–injected, chemotherapy-treated IG mice lost significantly more weight over the course of chemotherapy than GI mice, which in turn lost more weight than GG mice (IG > GI > GG, p values = 0.01; Table 1).

Experiment 2.
For tumor cell vehicle–injected, chemotherapy-treated mice, survival probability for IG mice was significantly less than for both II and GG mice (IG < II, {chi}2 = 7.626, p < .01 and IG < GG, {chi}2 = 5.752, p < .05) and marginally less than for GI mice ({chi}2 = 2.812, p = .094; Figure 4, B). Similarly, analysis of body weight loss over the course of chemotherapy revealed a significant group-by-days interaction (F(3,52) = 3,918, p = .01); IG mice lost significantly more weight than mice in all other housing conditions (IG > II = GG = GI, p values < .01; Table 1). It is possible that the decreased survival probability in tumor cell vehicle–injected, chemotherapy-treated IG mice was due to a poor host response to chemotherapy (possibly reflecting greater toxic side effects of chemotherapy), at least as assessed by body weight loss.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGMENTS
 REFERENCES
 
Overall our studies demonstrate that both tumor and host responses to chemotherapy are significantly influenced by experimental housing conditions and that these effects are independent of tumor growth rate at the time of chemotherapy initiation and, at least in terms of host response to chemotherapy, are independent of tumor burden. Importantly, these data also demonstrate that the temporal relationship among formation of housing conditions, tumor cell injection, and chemotherapy initiation plays a critical role in determining the direction and magnitude of the effects of social housing conditions on both tumor growth rate and chemotherapeutic efficacy.

If chemotherapy was initiated 1 day after tumor cell injection and formation of social housing conditions (experiment 1), a time when tumor burden is undetectable (similar to the adjuvant situation in humans), social housing condition did not influence tumor response to chemotherapy. That is, no tumor masses were palpable for up to 70 days after chemotherapy initiation, suggesting that chemotherapy was equally effective in containing tumor growth in mice in all housing conditions. Moreover, there were no significant differences in overall survival probability among mice in the different housing conditions. However, host responses to chemotherapy were better in GI and GG mice than in IG mice; GI and GG mice lost less weight than IG mice. If chemotherapy was initiated 1 day after formation of social housing conditions but approximately 14 days after tumor cell injection (experiment 2), a time when tumors weigh approximately 1 g and are growing at similar rates, GI mice showed longer tumor growth delay and lost less weight than IG and II mice. However, as in experiment 1, overall survival probability was not significantly different among mice in the different housing conditions.

The present data are in contrast to those of our previous study (41), in which experimental housing conditions were formed immediately after tumor cell injection and chemotherapy was initiated 14 to 18 days later, at a time when tumors weighed 1 g but were growing at different rates. Under those conditions, IG mice had a better tumor response to chemotherapy (longer tumor growth delay), a better host response to chemotherapy (less weight loss, unpublished results), and a greater overall survival probability than GI mice.

The finding that social housing condition did not influence tumor response to chemotherapy if chemotherapy is initiated when tumor burden is undetectable was not entirely surprising. It is recognized that when tumor burden is small, there is a greater chance for drugs to eradicate tumor cells, possibly because of the presence of fewer cells or proximity of the blood supply to the tumor cells and thus greater exposure of the cells to cytotoxic drugs. Furthermore, it is less likely that alterations in host physiological profiles (eg, endocrine or immune activity) could influence the development of tumor cell populations resistant to chemotherapy (56–58). Nevertheless, taken together our data demonstrate that altering the timing of chemotherapy initiation relative to tumor cell injection and formation of experimental housing conditions significantly influences both tumor and host responses to chemotherapy.

Altering the temporal relationship between tumor cell injection and formation of experimental housing conditions also differentially affects SC115 tumor growth rate, assessed in drug vehicle–treated mice. Data from both our initial study (41) and experiment 1 of the present study demonstrate that if social housing conditions are formed immediately after SC115 tumor cell injection, GI mice have significantly faster tumor growth rates than IG mice and GG mice have intermediate tumor growth rates. In contrast, if mice remain in their original individual or group housing conditions after tumor cell injection and experimental housing conditions are formed approximately 14 days later, as in experiment 2 of the present study, II mice have significantly faster tumor growth rates than both IG and GG mice, whereas GI mice have intermediate tumor growth rates. Interestingly, it seems that the differential tumor growth rates observed in drug vehicle–treated mice from the different experimental housing conditions cannot be used to predict tumor response to chemotherapy. In our previous study (41), mice that had the slowest tumor growth rates had the best tumor response to chemotherapy (longest tumor growth delay), whereas in the present study mice that had intermediate tumor growth rates (GI) had the longest tumor growth delay.

The differential effects of social housing condition on both tumor growth rates and chemotherapeutic efficacy among our experimental paradigms may be due, in part, to the differential timing of acute daily novelty stress relative to formation of experimental housing conditions, tumor cell injection, or initiation of chemotherapy. Although in both the present and our previous (41) studies, novelty stress was initiated 1 day after formation of experimental housing conditions, in the previous study this occurred 1 day after tumor cell injection and approximately 14 to 18 days before initiation of chemotherapy, whereas in the present study this occurred either 1 day or approximately 15 days after tumor cell injection and concurrently with the initiation of chemotherapy. Previous data have demonstrated that the timing of a stressor relative to tumor cell injection or tumor induction (eg, 7,12-dimethylbenz[a]anthracene [DMBA]- or N-methylnitrosourea [NMU]-induced tumors) can significantly affect tumor growth rates or tumor counts (29, 34) as well as endocrine levels and immune activity (28, 32, 59). Modifying influences of hormone levels and immune activity at the level of both the tumor and the host have been shown to alter tumor growth rates as well as the cytotoxic and toxic side effects of chemotherapeutic agents (32, 53, 60–66). Therefore, it is possible that the timing of experimental variables in relation to each other, that is, formation of experimental housing conditions, daily novelty stress, tumor cell injection or initiation of chemotherapy, differentially altered physiological profiles (eg, endocrine levels or immune activity) and thus played a role in mediating the differential tumor growth rates, the differential tumor responses to chemotherapy, or the differential toxic side effects of chemotherapy between our present and previous (41) studies.

The mechanisms underlying the differential SC115 tumor responses to chemotherapy are unknown at present. Psychosocial stressor–induced or chemotherapy-induced changes in endocrine function may be involved. We have shown previously that for male mice in our standard laboratory housing condition (group housed and not subjected to daily novelty stressors), SC115 tumor response to adriamycin and cyclophosphamide can be modulated by altering the level of exogenous testosterone administered after castration (53). It has also been shown that the anti-tumor effects of cyclophosphamide on ascitic Ehrlich tumors in mice can be suppressed by increased activity of endogenous or exogenous corticosterone through acceleration of drug metabolism (67). Furthermore, we have demonstrated that over the first 7 days after tumor cell injection and formation of experimental housing conditions, basal testosterone levels are higher in GI than in IG mice, whereas basal corticosterone levels are higher in IG mice than in mice in all other housing conditions (51). Therefore, in the present study, altered hormone profiles among mice in the different housing conditions at the time of chemotherapy initiation may have differentially affected tumor responses to chemotherapy.

Differential tumor response to chemotherapy may also be mediated through changes in immune function. Such changes may occur either directly through chemotherapy-induced changes in immune function or indirectly through psychosocial stressor–induced changes in hormonal activity that in turn alter immune function. We have shown that the SC115 tumor differentially stimulates natural killer cell activity in mice in the different housing conditions at 7 days after tumor cell injection and formation of experimental housing conditions (68, 69). In addition, preliminary evidence from our laboratory suggests that the SC115 tumor stimulates a tumor-specific cytolytic immune response (unpublished data). Several studies have shown that chemotherapy treatment is optimized when combined with an increase in immune activity (61, 62, 70–73). Thus, differential immune activity in mice in the different experimental housing conditions could alter tumor response to chemotherapy. Alternatively, chemotherapy in itself may differentially affect both endocrine and immune activities of mice in the different housing conditions, thereby altering tumor response to chemotherapy. In animal studies, both adriamycin and cyclophosphamide have been shown to affect the immune and/or endocrine responses (47, 74, 75).

Body weight change has been shown to influence the effectiveness of chemotherapy (76–78), possibly through alterations in hormone (eg, glucocorticoids and insulin) levels that may modulate, directly or indirectly, the activity of drug-metabolizing enzymes (9, 10, 79–81) or change the growth kinetics of tumor cells (53, 60, 82). Similar to other studies (83–85), our studies demonstrate that body weight loss over the duration of chemotherapy is inversely proportional to the tumor response to chemotherapy. In our previous study (41), IG mice lost less weight and had better tumor response to chemotherapy than GI mice, and in experiment 2 of the present study, GI mice lost less weight and had a better tumor response to chemotherapy than mice in other housing conditions.

In the present study, increased weight loss and reduced survival probability experienced by IG mice may have been influenced by the increased fighting that occurs when the IG condition is formed. Previously we showed that 1 day after formation of experimental housing conditions, fighting and defensive behaviors are significantly increased in IG mice compared with mice in all other housing conditions (44). We (40, 44) and others (38) have suggested that fighting may represent a form of coping response that may play a role in reducing tumor growth rate and possibly increasing chemotherapeutic efficacy in established social groups (41). However, a single experience with a stressor in the form of social defeat has been shown to have marked physiological consequences lasting from hours up to weeks (86) and is characterized by increased corticosterone secretion together with impaired production of sex steroids (eg, testosterone) and suppressed immune function (86–88). Thus, the initial physiological effects of fighting on the day of chemotherapy initiation could play a role in increasing the probability of weight loss and toxic effects of chemotherapy and in decreasing survival probability.

Stressor-induced changes in hormones and cytokines may influence the toxic side effects of drugs, possibly including chemotherapeutic agents (47, 68, 89–92). We and others have demonstrated that for mice allowed to adapt to new social housing conditions, the impact of the change in social housing condition on endocrine and immune functions is reduced (44, 59, 86, 88). The present study demonstrates that if chemotherapy is initiated 1 day after the formation of experimental housing conditions (at a time when hormone and immune activity is differentially altered among social housing conditions; Refs. 51, 68, and 69), IG mice lose more weight and have a lower survival probability compared with GI or GG mice. Conversely, if chemotherapy is initiated 14 to 18 days after formation of social housing condition (at a time when hormone and immune activity may be similar among social housing conditions), mice in the IG housing condition lose less weight and have a higher survival probability compared with GI mice (41). By 14 days after the initiation of chemotherapy, social hierarchies among mice in the IG housing condition have become established and mice have adapted to the new housing condition, as evidenced by the reduction in fighting among mice within the IG housing condition (44). Thus, different physiological profiles may exist between IG mice rehoused 1 day before initiation of chemotherapy and those rehoused 14 days before chemotherapy; as a consequence, differential tumor and host responses to chemotherapy were observed.

In summary, the present study and our previous study (41) together demonstrate that social housing conditions can significantly influence the efficacy of chemotherapy and highlight the importance of the temporal relationship between formation of social housing conditions and initiation of chemotherapy on chemotherapeutic efficacy. These studies suggest that the effects of social housing conditions on chemotherapeutic efficacy may be independent of tumor growth rate at the time of chemotherapy initiation and, at least in terms of host response to chemotherapy, are independent of tumor burden. Finally, these studies highlight the possible impact of social housing condition on the complex interrelationship among the host environment, tumor growth, and chemotherapeutic efficacy. Although it is difficult to extrapolate from the animal to the human situation, these data may help to emphasize the role that psychosocial stressors may play in the often unpredictable and highly variable differences in tumor responses to chemotherapy as well as in the toxic side effects of chemotherapy observed among cancer patients.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
REFERENCES
 
Supported by Grant CA73446 from the National Cancer Institute, National Institutes of Health. L.R.K. was supported by the Roman M. Babicki Scholarship for Medical Research. We thank Darcy Wilkinson and Angie Lee for assistance in running the experiments.

Received for publication February 27, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 

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L. R. Kerr, H. N. Andrews, K. S. Strange, J. T. Emerman, and J. Weinberg
Temporal Factors Alter Effects of Social Housing Conditions on Responses to Chemotherapy and Hormone Levels in a Shionogi Mammary Tumor Model
Psychosom Med, November 1, 2006; 68(6): 966 - 975.
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