H2-antagonists in the treatment of colon and breast cancer

seminars in CANCER BIOLOGY, Vol. 10, 2000: pp. 3–10 doi: 10.1006/scbi.2000.0301, available online at http://www.idealibrary.com on

H2-antagonists in the treatment of colon and breast cancer Elaine Bolton, Julie King and David L. Morris∗

Levels of histamine in cancer patients

Several clinical trials have now been carried out with histamine type 2 receptor antagonists in cancer patients often as an adjunct to surgical resection of the primary tumour. While promising results have been obtained in some groups of patients with gastrointestinal cancer, with increased survival and evidence of increased immunological recognition of tumour, results are less encouraging for breast cancer. This may be due to differences in the levels of histamine or the role of histamine in growth of these different tumour types.

Levels of histamine in the blood of cancer patients are often lower than in age-matched controls.8 The decreased level of histamine is associated with decreased numbers of basophils in the blood20 and may provide an indication of disease progression.8 In contrast, one other study found high levels of histamine in the blood of newly diagnosed cancer patients34 compared to normal controls. The discrepancy in these studies may reflect differences in the extent of disease as the latter group of investigators also demonstrated decreased blood histamine levels in another group of patients with untreated terminal cancer. When histamine is measured in the tumour tissue, high concentrations can be detected, particularly in colorectal and breast cancer. In colorectal cancer tissue, there is a large range in the levels detected (<1–86 µg g−1 tissue) though some of this variability may result from differences in sample preparation and the lability of histamine. In addition, we have found that the reproducibility of measurement in tumour tissue is not as great as in experimental beef specimens spiked with histamine, suggesting that there is increased breakdown or sequestering of histamine in tumour tissue preparations. With our method alone the range was 0.3–20.6 µg g−1 histamine in tumour tissue taken from the leading edge of the tumour without any necrotic tissue. The median (SE) level measured was 8.4 µg g−1 in colorectal cancer tissue (equivalent to 7.6 × 10−5 M) and 8.0 µg g−1 in healthy colorectal tissue.39 Others have measured median (SE) histamine levels of 1.2 (0.3) µg g−1 in tumour tissue and 1.7 (0.5) µg g−1 in normal colorectal tissue23 or 85.94 (10.54) µg g−1 in tumour tissue compared to 30.45 (2.12) µg g−1 in adjacent healthy colorectal tissue.13 A similar variation in the level of histamine is seen in breast cancer. Chanda and Ganguly13 found the median (SE) histamine content in breast cancer to be 82.06 (12.02) µg g−1 compared to 32.55 (2.97) µg g−1 in adjacent normal tissue. Garcia-Caballero et al found

Key words: histamine / histamine antagonists / tumour infiltrating lymphocytes / cell-mediated immunity c 2000 Academic Press 

Introduction The use of histamine type 2 (H2) receptor antagonists in cancer has been the subject of research for approximately 20 years. The interest in these drugs for the treatment of cancer is based in part on the finding that high concentrations of histamine can both stimulate the growth of some tumour cells as well as suppress many immune functions. While lower concentrations of histamine do not appear to be deleterious and may even prevent the growth of tumours, the tumour-promoting effects of high concentrations of histamine appear to be predominantly mediated via the H2 receptor.

From the University of New South Wales, Department of Surgery, St George Hospital, Kogarah, Sydney, NSW 2217, Australia. *Corresponding author. c 2000 Academic Press 1044–579X / 00 / 000003+ 08 / $35.00 / 0

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E. Bolton et al

melanoma or prostate cancer cell lines.47 Histamine is also produced endogenously in some tumour models and inhibition of de novo histamine synthesis by the irreversible inhibitor monofluoromethylhistidine (MFMH) retards the growth of these tumours.14 Administration of exogenous histamine to tumourbearing animals can either inhibit or stimulate tumour growth. When histamine is administered to immunodeficient nude mice bearing subcutaneous human xenografts of colorectal cell lines, there is either no effect or a stimulation of tumour growth relative to saline-treated controls.1 The effect can be predicted from in vitro proliferation assays with histamine. The stimulatory effect of histamine can be reversed by administration of cimetidine. In syngeneic animal models bearing subcutaneous tumours of hepatoma cell lines, administration of histamine alone tends to inhibit tumour growth.11 The inhibition of tumour growth may be mediated via H1 receptors as the addition of cimetidine has little effect. In support of this, in C3H and C57BL/6 mice with fibrosarcomas, histamine alone or histamine + metiamide (the only H2 receptor antagonist tested) gave best inhibition of tumour growth and metiamide increased survival. In contrast the H1 receptor antagonist, mepyramine, decreased survival.10 Early work with cimetidine demonstrated decreases in the growth of tumours in animals that have not received exogenous histamine. Fifty or 100 mg kg−1 /day, but not 25 mg kg−1 /day, cimetidine decreased growth of ovarian carcinoma xenografts in nude mice and this was associated with increased in vitro lysis of tumour cells by splenocytes from tumour-bearing animals.30 The growth regulatory effect of cimetidine is also seen in many syngeneic mouse models including the EL4 lymphoma and 3LL Lewis lung carcinoma lines in C57BL/6 mice, as well as the NK resistant fibrosarcoma line MC43 in C3H mice.24, 37 Tumour growth and metastasis is reduced and survival increased with doses around 100 mg kg−1 /day cimetidine in the drinking water24 without addition of exogenous histamine. This concentration of cimetidine produces a plasma level of 0.16–0.35 µg ml−1 that is comparable to the dose achieved in a human being taking 300 mg orally. The H2 antagonists; metiamide, ranitidine and cimetidine, can also control growth of carcinogen-induced colon cancer in rats as measured by decreased mitotic rate44 as well as tumour invasion.2

the median (SE) content to be lower in breast cancer tissue at 4.05 (27.0) µg g−1 compared to 6.1 (0.46) µg g−1 in adjacent healthy tissue although the variation in tumour tissue was great.22, 23 We have reported median levels of 5.4 (1.3) µg g−1 in tumour tissue and 1.3 (0.4) µg g−1 in adjacent normal breast tissue.40 There are several possible sources of histamine in tumours. There is increased expression of histidine decarboxylase, the enzyme that catalyses histamine synthesis, during proliferation of many cell types including tumour cells grown both in vitro and in vivo.6 Elevated levels of HDC, much higher than normal tissue, have been measured in colorectal cancer.21 This suggests that there is histamine production by tumour cells or inflammatory cells infiltrating the tumour. However, it is possible that histamine produced by de novo histamine synthesis may be utilized within the cell rather than being released in large quantities or may be rapidly degraded once released. Mast cells or basophils might represent a source of histamine within the tumour environment. Mast cell infiltration is associated with a poor prognosis in colorectal cancer19 though it is not clear if this is due to release of histamine or other activities. Overall, there does appear to be sufficient production of histamine in the tumour environment to affect cellular activity.

Histamine as a cancer cell growth factor The ability of histamine to alter the growth of certain cancer cell lines both in vitro and in vivo has been known for some time. In vitro, histamine at concentrations between 10−8 and 10−7 M has been reported to stimulate the proliferation of some, but not all, human colorectal cell lines though the response is somewhat variable.1, 32, 45 In our hands the differences in the sensitivity of these cell lines to stimulation by histamine appear to be related to expression of the H2 receptor as judged by cAMP accumulation following incubation with histamine. In addition, the H2 antagonist cimetidine can prevent the effects of histamine on tumour cell proliferation. There have, however, been reports that in some breast cancer and melanoma cell lines H2R signal transduction occurs via second messengers normally associated with the H1 receptor,15 though this is certainly not the case for all transformed cells.46 Addition of histamine to cultures of the gastric tumour cell line, MKN45 also results in increased cell growth and cAMP accumulation45 but not for breast, 4

H2-antagonists in the treatment of colon and breast cancer

Immunomodulatory role of histamine

Clinical trials of H2 receptor antagonists in cancer

High concentrations of histamine suppress many immunological functions including lymphocyte adhesion,27 cytotoxicity,25 cytokine production12, 16 and proliferation with most effects being prevented by addition of cimetidine or other H2 antagonists. It is possible that reversal of immune suppression is one of the major mechanisms by which cimetidine reduces tumour growth. It has been known for some time that histamine can reduce lymphocyte infiltration into inflammatory sites. Lymphocyte infiltration into the site of inflammation associated with a delayed-type hypersensitivity reaction was inhibited by twice daily injection of 0.1–10 mg kg−1 histamine for two days and also by H2 agonists but not H1 agonists. Cimetidine and ranitidine both reversed the suppression caused by histamine42 confirming dependence on the H2 receptor. We have recently investigated the role of histamine in regulating lymphocyte infiltration into MC-38 colorectal tumours grown subcutaneously in C57BL/6 mice. There are only minor effects of histamine and cimetidine on the growth of this cell line in vivo over the first 21 days. Histamine does, however, reduce the number of lymphocytes infiltrating into the tumour (TIL) and this effect is reversed with cimetidine. Cimetidine alone has little effect on the number of TIL. The number of TIL appears to show an inverse correlation with the level of interleukin-6 and IFNγ mRNA in the tumour though the role of these cytokines in this model has not been determined (manuscript in preparation). Interestingly, although downregulation of interleukin-2 production may be one of the major mechanisms of histamine-induced immunosuppression, we were unable to detect IL-2 mRNA by either ribonuclease protection assay or RT-PCR in the majority of MC-38 tumours, even after administration of cimetidine at 200 mg kg−1 /day. However, administration of recombinant human IL-2 to MC-38 bearing mice resulted in a greater infiltration of the tumour by lymphocytes and decreased tumour growth (unpublished results). It is possible then, that prevention of the immunosuppressive effects of histamine by administration of cimetidine, together with IL-2 or other immune stimulants, may produce much greater immunological control of tumour growth and subsequent survival.

The ability of cimetidine to increase survival of cancer patients was first described by Tonnessen et al in 1988.43 Cimetidine was administered at 400 mg twice daily following resection of gastric adenocarcinoma for 2 years or until death as part of a randomized placebo-controlled trial. Survival rates were higher in the cimetidine group at 1 year (45% compared to 28% with placebo), 3 years (13% compared to 7%) and at 5 years (2% compared to 0%). We then carried out a small randomized controlled study in which cimetidine was administered peri-operatively (7 days pre-operatively and 2 days post-operatively) to patients undergoing resection for primary colorectal cancer. Cimetidine prevented the immunosuppressive effects of surgery on in vitro lymphocyte function and on cell-mediated immunity measured by skin tests to common recall antigens.5 After 3 years, a survival advantage of 35% in cimetidine-treated Dukes A, B and C patients was reported.3 We then measured TIL in the resection specimens and found that TIL presence correlated with survival, as previously reported,28 but also that cimetidine increased the number of patients with a prominent TIL infiltrate (67% compared to 24% with placebo).4 Two other groups have supported the trend to survival advantage reported in our preliminary study. Svendsen et al found a trend to increased survival in patients with Dukes C tumours but not those with Dukes B tumours when 400 mg cimetidine twice daily was administered post-operatively.41 In a group of patients administered 800 mg cimetidine and 5-FU or 5-FU alone for 1 year post-resection, there was a significant increase in the 3.9 year survival in the cimetidine-treated group (96.3%) compared to controls (53.3%).33 We have since carried out a larger trial of cimetidine in patients with colorectal cancer. A small but not statistically significant trend to survival advantage was seen in patients treated with 800 mg cimetidine twice daily. In the study we separated patients on the basis of the presence of replication errors (RER) as determined by immunohistochemistry and there was a significant improvement in survival with greater response in patients with replication error negative tumours.29 Again, there was an effect on the number of patients with a conspicuous lymphocyte infiltrate as estimated by scoring haematoxylinand eosin-stained histological sections.18 However, when we counted the number of peri-tumoural CD3 5

Tumour Type

primary astric

primary gastric

primary gastric

primary gastric

Tonnesen et al Lancet 1988; 2 (8618) 990–2

Hallissey et al GUT 1996 Abst. Langman et al BJC in press 1999

Wotherspoon et al BJS 1997;84: 1168–9

Primrose et al GUT 1998;42(1): 9

ranitidine 150 bd

ranitidine 150 mg/cont IV at op. and peri-op. then 150 mg for 2 yrs

cimetidine 400 mg or 800 mg bd

cimetidine 400 bd for 2 yrs

H2 antagonist

Post- or nil op. (radical or palliative resection)

intra- and post-op.

immediate post-op. or decision of no op.

Timing of study treatment (Rx)

Clinical trials of H2 antagonist treatment for gastric cancer

Citation

Table 1.

222

159

442

181

n=

p = 0.22

331 vs 187∗

280 vs 344∗ p = 0.62

79 vs 80

11 mth 12 mth p = 0.18

41 mths median f/up

p = 0.02

450 vs 316∗

Rx vs Control median survival days*

Stage VI Rx vs cont 313 vs 134

RCT multicentre

RCT multicentre

RCT multicentre

overall = p > 0.05 dose = p > 0.05 stage = p > 0.05

n = 28 not suited for surgery = p > 0.05

Randomized controlled trial (RCT) multicentre stratified by gastric surgery procedure

Study type

Rx vs control 1 yr survival 45% vs 28% 4 yr survival 9% vs 3%

Subgroup

E. Bolton et al

6

Tumour Type

primary colorectal

primary colorectal

primary colorectal

primary colorectal

primary colorectal

metastatic colorectal

metastatic colorectal

Svendsen et al Dis Col Rect 1994;38(5)514–18

Adams et al Lancet 1994;1:1768–9

Matsumoto et al Lancet 1995; 346:115

Nielsen et al GI Cancer 1998; 2(3) 227–33

Kelly et al Cancer 1999.85(8)1658–63

7

Nielsen et al GI Cancer 1996;1:183–90

King et al 1997 ACOS Abst. Asian J Surg 2000 (in press)

ranitidine 150 mg bd for 2 years

ranitidine 300 mg bd for 3 mth then open ranitidine

cimetidine 800 mg od 400 mg od

ranitidine intra-op. then 150 mg bd for 5 yrs

Cimetidine 800 mg od for 1 yr

cimetidine 400 mg bd

cimetidine 400 mg bd

H2 antagonist

post-liver surgery or with IA or IV 5FU

4 weeks post primary resection with synchronous liver mets

Pre-op. for 5 days

Pre-op.

Post-op. resection having adjuvent 5FU

Pre-op. for 7 days and 2 days postop.

1 week post resection or laparotomy

Timing of study treatment (Rx)

117

25

125

686

64

34

192

n=

Clinical trials of H2 antagonist treatment in primary and metastatic colon cancer

Citation

Table 2.

604 vs 455∗ p = 0.2

p < 0.03

by liver disease Rx = ns n = 17 with good prognosis liver disease and CMI p = 0.01

ranitidine Rx: NK cell p < 0.02 LAK cell p < 0.03 IFN-induced NK cell p < 0.05

800 mg trend to increased survival p = 0.2 in RER negative tumours p = 0.04

p = 0.2

between groups

A to D Dukes’‚stage = ns

p = 0.54

RCT pilot

Stage = ns

RCT

RCT for 3 months then all Rx to death

RCT

RCT multicentre Suspended post 40 mth interim analysis

RCT multicentre

Randomized controlled trial (RCT) multicentre pilot

n = 148 curative intent p = 0.43 n = 41 non-curative p = 0.21

colon %: 96.3 vs 68 rectal %: 100 vs 53.3

Study type

Subgroup

31 month mean f/up 3.9 yr survival p = 0.025

30 month median f/up p = 0.17 3 yr survival 93% vs 59%

curative intent trend to cancer specific Dukes C p = 0.11

Rx vs Control median survival days∗

H2-antagonists in the treatment of colon and breast cancer

E. Bolton et al

positive lymphocytes using image analysis, no statistically significant difference could be detected between groups. In contrast to the increase in survival, albeit small, which is seen with cimetidine in the studies described above, some studies with cimetidine have shown no effect at all. In a study of 442 gastric cancer patients administered 400 or 800 mg cimetidine twice daily, there was no effect on survival with a median followup of 44 months.26 In addition, we have examined survival, lymphocyte infiltration and tumour kinetic index determined from expression of proliferating cell nuclear antigen in 72 breast cancer patients randomized to either 400 mg cimetidine or placebo twice daily. Cimetidine had no effect on any of the parameters tested.7, 17 Several groups have investigated the use of ranitidine, which is a more potent antagonist than cimetidine, on parietal H2 receptors. In the studies of 222 patients with advanced gastric cancer38 and 159 patients with gastric cancer treated with ranitidine, there were no statistical survival differences reported.48 Nielsen’s study of ranitidine treatment long term studied 686 patients with primary colorectal cancer, but at 40 months follow-up no difference in survival was found.36 It could be supposed that the Primrose and Wotherspoon studies were underpowered but the numbers were comparable with Tonnesen’s43 trial where a 2 year trend to survival with 22% cimetidine treatment versus 13% placebo was achieved.43 One of the differences in these studies was the administration route for ranitidine. Tonnesen used intravenous cimetidine, Wotherspoon used intravenous then oral ranitidine while Primrose used oral ranitidine only.38 However, a significant survival advantage was reported with ranitidine in a small study of 25 patients with liver metastases from colorectal cancer.35 There was also improved immune reaction judged by natural killer cell and lymphokine-activated killer cell activity in patients treated with ranitidine.35 In a study of 117 patients with colorectal liver metastases treated long term with ranitidine we found no statistical difference in survival between groups, but in those patients who had low volume liver disease and poor cell-mediated immunity, there was significantly increased survival (manuscript in preparation). Of interest are studies in which H2 antagonists have been used in combination with histamine. This combination aims to prevent the immunosuppressive effects of high concentrations of histamine acting via the H2 receptor and promote the vascular, anti-

tumour effects associated with H1 receptor signalling. In a small group of advanced cancer patients in whom resection was impossible and previous treatment had failed, survival was significantly greater (172 ± 113 days) in the treated group compared to nontreated patients (26 ± 16 days).9

Current role for H2 antagonists in the treatment of colon cancer While H2 antagonists have clearly had some positive effect on outcomes for gastrointestinal cancer patients, their benefits may be limited to certain subgroups of patients. While the factors determining their usefulness are not known, we have observed most effect in patients with poor pre-operative cell-mediated immunity. It is not known if this is related to high levels of histamine in these patients. It seems likely that further improvement in treatment might be gained by combining the use of H2 antagonists, to block the immunosuppressive effects of histamine, with other immune stimulants to promote greater immunological control of tumour growth or dissemination.

Acknowledgements The work of the authors was funded by grants from the National Health and Medical Research Council of Australia and the St George Bank, Australia.

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