Animal models for liver metastases of colorectal cancer: research review of preclinical studies in rodents

Liver metastases of colorectal carcinoma occur in about 50-60% of patients. To improve survival of these patients, there is an urgent need for new treatment strategies. For this purpose, the availability of a preclinical model to develop and test such treatments is mandatory. An ideal animal model for studying liver metastases of colorectal origin should mimic all aspects of the metastatic development in humans and be practical, predictable, and optimal in terms of ethical considerations. Thus far, no model has been developed which satisfies all these conditions. As a consequence, choosing an animal model for the study of liver metastases requires compromises and choices about the necessary characteristics that depend on the purpose of the intended experiments. This overview addresses the advantages and disadvantages of different animal models used for research on experimental liver metastases of colorectal origin. Based on data available in literature, we conclude that heterotopic injection of undifferentiated syngeneic tumor cells in immunocompetent rodents covers most of the desired characteristics. Both subcapsular as well as intraportal injection will yield suitable models and the eventual choice will depend on the aim of the study.     

How are we treating patients with hepatic colorectal metastases in Sydney?

Introduction: Colorectal cancer is common. At presentation 25% of patients have established hepatic metastases and overall at least half will develop hepatic metastases. Many different therapeutic options have been proposed. This study evaluates the current resources available and patterns of care for patients with hepatic colorectal metastases in the Sydney metropolitan area. Methods: Prospective data were collated describing all patients presenting to any one of nine hospitals within the Sydney metropolitan area in a 12‐month period, diagnosed with hepatic metastases. The data included patient demographics and background, treatment of the primary tumour, diagnosis and treatment of the hepatic metastases and histopathology both of the primary and of the hepatic metastases. Results: There were 194 patients in the study. Most when diagnosed with hepatic colorectal metastases were independent, active, retired and usually had existing social supports. The majority had had their primary colorectal cancer resected and were later treated with systemic chemotherapy. Conclusions: This study highlights the need for a comprehensive multicentre, prospective data collection of patients with hepatic metastatic disease. This would clarify the effectiveness or otherwise of the health system caring for such patients and provide additional information for the development and implementation of guidelines.     

Resecting large numbers of hepatic colorectal metastases

Background : Despite the widespread use of surgical resection as a treatment for hepatic colorectal metastases, the value of resecting more than three metastases remains controversial. It was the objective of this study to determine if resection of larger numbers of metastases affects patient survival. Method : The survival of 123 consecutive patients who underwent curative hepatic resection for colorectal metastases between 1989 and 1999 by a single surgeon was analysed retrospectively. Kaplan–Meier survival statistics and Cox regression were used to determine the factors that affected survival, and logistic regression was used to determine the factors that affected the risk of recurrence of hepatic disease. Results : The median survival rate for the whole group of patients was 38 months, with 1, 3 and 5 year survival rates of 88%, 53% and 31% respectively. The survival rate of patients undergoing resection of four to seven metastases (n = 22; 5 year survival = 39%) was not significantly different to that of patients undergoing resection of one to three metastases (n = 91; 5 year survival = 30%), P = 0.9. Age, sex, primary cancer site, hepatic disease distribution, resection margins and adjuvant hepatic arterial chemotherapy (HAC) did not affect survival. Local invasion of the hepatic metastases (relative risk (RR) = 2.9; P = 0.001) and hepatic disease recurrence (RR = 2.1; P = 0.007) were the only factors that independently affected survival. Local invasion of the hepatic metastasis was the only factor associated with an increased risk of hepatic recurrence (RR = 2.8; P = 0.03). Adjuvant HAC did not affect the risk of hepatic recurrence (RR = 1.5, P = 0.4). Conclusion : Although there are no randomized trials that quantify any survival benefit from resection of liver metastases, the comparison of our results with well documented historical evidence indicates that surgical resection of up to seven colorectal liver metastases can result in a significant survival benefit.     

Selective internal radiation therapy with 90Y microspheres for colorectal liver metastases: single-centre experience with 100 patients

BACKGROUND: Many patients with colorectal liver metastases die from liver-only disease. Selective internal radiation therapy (SIRT) is an evolving method suitable for treating patients with non-resectable metastatic liver disease. METHODS: One hundred patients with advanced colorectal liver metastases were treated with SIRT. A single dose of between 2.0 and 3.0 GBq of (90)Y microspheres was given into the hepatic artery either by a surgically implanted portacath or a percutaneous femoral catheter. When a port was used (n = 87), SIRT was followed by hepatic arterial chemotherapy with 5-fluorouracil. RESULTS: Treatment-related morbidity occurred in 11 patients. Responses to SIRT were assessed by serial computed tomography scans and carcinoembryonic antigen (CEA) measurement. Median CEA level 3 months after SIRT (expressed as percentage of initial CEA) was 18%. Only 5 of 80 patients (6.25%) scanned at 3 months showed disease progression. Survival was significantly more in those who experienced a good tumour marker response and in those who were slow to develop extrahepatic disease. Survival was independently influenced by the use of ongoing hepatic arterial chemotherapy, the extent of liver involvement and the lymph node status of the original primary tumour. CONCLUSION: Selective internal radiation therapy is a very effective and well-tolerated regional treatment for colorectal liver metastases, which should be considered for those with liver-only metastatic disease.     

THE AETIOLOGY AND MANAGEMENT OF HEPATIC METASTASES

Hepatic metastases are a common event in the metastatic spread of primary tumours and indicate advanced disease. However, the presence of hepatic metastases does not necessarily imply incurability; in selected patients resection of hepatic metastases may result in 5-year survival rates of 25–35%, usually in patients with colorectal liver metastases in whom solitary metastases are more frequent than with other primary tumours. However, hepatic metastases from Wilm's tumours, adrenal tumours, renal cell carcinoma, and neuroendocrine tumours may also be resected with similar success rates. A poor prognosis after resection of hepatic metastases is likely when there are more than three metastatic deposits, involved resection margins (often as a result of ‘wedge’ resections), when there is extrahepatic disease, or nodal involvement at the primary tumour site. Cyto-reductive procedures may provide excellent palliation and possibly long-term survival in selected patients with hepatic metastases unsuitable for resection. However, further study is required to establish the appropriate role for these treatments.     

Aggressive repeat liver resection for hepatic metastases of colorectal carcinoma

Although hepatectomy for liver metastases from colorectal carcinoma is an effective treatment, recurrence in the liver is still the most common site after hepatectomy. Thirty patients underwent hepatectomy for hepatic metastases and 17 of them had recurrence in the remnant liver during the following 12-year period. Six of the 17 patients underwent a removal of isolated hepatic recurrences. Two of the six patients underwent a third hepatectomy, and three patients underwent partial lung resection on a total of five occasions. There were no operative deaths while complications after a third hepatectomy contributed to a high morbidity rate of 40 per cent. The mean length of survival of the six patients was 28.5 months from the second hepatectomy. The prognosis of the six patients who underwent a repeat hepatectomy was significantly better than that of patients with unresectable recurrence after an initial hepatectomy (p<0.01). The overall 5-year survival of 29 patients excluding one inhospital death was 44.7 per cent. Our results reveal that aggressive removal of isolated and resectable recurrent disease has the potential to improve the prognosis of selected patients with metastatic cancer.     

A prospective evaluation of hepatic resection for colorectal carcinoma metastases to the liver: Follow-up report

Single institution studies of hepatic resection have implied that some subsets of patients with metastases from colon and rectum adenocarcinoma can be cured by surgery. However, it is unknown how such patients can be selected and what, in fact, the ultimate cure rate is. The objective of this multi-institutional study was to define in a prospective manner how many patients predicted to have resectable liver metastases actually could undergo curative resection and what the disease-free and overall survival were. A prospective 15-institution treatment plan included all patients who were predicted to have resectable metastases from colon and rectum cancer primaries. Results were compared among patients who underwent successful resection, patients who underwent resection with pathologically defined inadequate margins, and patients who underwent exploration but were found at surgery not to have resectable liver metastases. Fourteen institutions throughout North America and one in Milan who were members of the Gastrointestinal Tumor Study Group at the inception of this protocol in July of 1984 participated in the study. The patient population consisted of all those with metachronous or synchronous metastases from colon or rectum adenocarcinoma seen during a consecutive 3 1/2 year period with protocol registry at the time liver metastases were predicted to be isolated and resectable. Intervention consisted of the application of standard preoperative screening tests, abdominal exploration, and resection of all patients who had liver-only surgically resectable disease. The main outcome measures were: Accuracy of preoperative staging, acute and chronic operative morbidity, and disease-free, as well as overall, survival among the three treatment groups. The minimum follow up on all surviving patiens after curative resection was 2.2 years, with a median follow up of 3.2 years. Median survival times for patients receiving curative and noncurative resections and for those receiving no resection were estimated to be 35.7, 21.2, and 16.5 months, respectively. No statistically significant difference in the survival distribution of the noncuratively resected or the non-resected patients was observed. The survival distribution of curatively resected patients remains statistically superior to the distribution of noncuratively resected patients and those receiving no resection (P=0.01). These results confirmed that, although liver resection for hepatic metastases from colorectal car cinoma is safe to do and presently constitutes the only standard curative treatment for potentially resectable disease, it ultimately cures few patients.     

Prognostic differences between oligometastatic and polymetastatic disease after resection in patients with colorectal cancer and hepatic or lung metastases: Retrospective analysis of a large cohort at a single institution

BackgroundLong-term survival data are lacking, and prognostic factors are not well-defined for patients with colorectal cancer and hepatic or lung metastases. This study evaluated the outcomes after resection of oligometastatic hepatic or lung metastases from colorectal cancer and sought to identify prognostic factors.MethodsWe retrospectively investigated 1,123 patients with colorectal cancer and hepatic or pulmonary metastases who underwent curative surgery between January 1991 and December 2016.ResultsOf the 1,123 patients, 719 had hepatic metastases, 287 had pulmonary metastases, and 117 had both. The 5-year overall survival rate was 52.3% in the hepatic metastases group, 70.4% in the pulmonary metastases group, and 71.4% in the hepatic and pulmonary metastases group (P < .001). In total, 1,045 patients had oligometastases (1–5 metastatic lesions in 1 or 2 organs) and 78 had polymetastases (≥6 metastases in 1 or 2 organs). Prognosis was significantly better in patients with oligometastases than in those with polymetastases. The 5-year overall survival rate was 59.0% in the oligometastases group and 35.3% in the polymetastases group (P < .001); the respective 5-year relapse-free survival rates were 37.5% and 11.6% (P < .001). Multivariable analysis identified predictors of both poor overall survival and relapse-free survival to be a high carcinoembryonic antigen level before the first metastasectomy, largest metastasis measuring ≥2 cm, polymetastases, and synchronous metastases.ConclusionPrognosis after curative resection was better in patients with oligometastatic colorectal cancer in the liver or lung than in those with polymetastases. Multidisciplinary decision-making strategies, including about surgery, should be based on number of metastases rather than their site.     

Aggregated colon cancer cells have a higher metastatic efficiency in the liver compared with nonaggregated cells: an experimental study

BACKGROUND: It remains unclear whether aggregated colon cancer cells have a higher tendency for metastasis formation than nonaggregated cells. Also, the absolute number of cancer cells required for hepatic metastasis remains undefined. The aim of the present study was to compare in the liver the metastatic efficiency of viable nonaggregated colon cancer cells versus cell aggregates for equivalent numbers of cancer cells. MATERIALS AND METHODS: DHD/K12/TRb colon cancer cells were administered through the portal vein in syngeneic male BD IX rats. Surgical exploration was performed 8 weeks after injection. Four groups of rats were injected with 0.25 or 0.5 x 10(6) DHD/K12/TRb viable cancer cells, either as single nonaggregated cells or as cell aggregates. RESULTS: Hepatic metastases were observed in 81% of the rats after intraportal injection of cell aggregates equivalent to 0.5 x 10(6) cancer cells. A significant lower metastatic efficiency was found after the injection of 0.5 x 10(6) non-aggregated, and 0.25 x 10(6) aggregated or nonaggregated cancer cells i.e., 16%, 32%, and 27%, respectively. CONCLUSION: Aggregated colon cancer cells have a higher metastatic efficiency in the liver compared with non-aggregated cells, although a critical number of cancer cells are necessary.     

Complete remission of disease for 5 years following initial and repeat resection of the liver for the removal of 22 metastases of colorectal origin

Although liver resection is accepted as the only available treatment that regularly produces long-term survival with possible cure in patients with colorectal carcinoma metastatic to the liver, controversy appears to exist regarding the surgical indication for patients with more than four nodules. Similarly, it may be arguable to perform a repeated hepatic resection for a patient who developed multiple recurrent liver metastases with a short disease-free period after the initial liver resection. During the last 7 years, we have adopted constantly the aggressive surgical approach to patients with colorectal carcinoma metastatic to the liver if the number of tumor nodules identified preoperatively were less than ten and irrespective of the length of disease-free period after the previous resection. Here we report on a patient who underwent hepatic resection twice at an interval of 3 months and in whom a total of 22 metastatic nodules (6 in the initial hepatic resection and 22 in the repeated resection) were removed. The patient is now alive and remains disease-free, 5 years after the first liver resection.     

Resection of hepatic metastases from colorectal cancer

Summary Background: The aim of this paper is to analyze our experience with liver resection for metastatic colorectal cancer and to evaluate the prognostic significance of various parameters. Methods: 40 consecutive patients treated with potentially curative liver resection between 1984 and 1996 were included. The prognostic significance of various parameters was evaluated with respect to survival. Univariate and multivariate analyses were performed for following factors: age, gender, site and stage and grading of the primary tumor, size of metastases, number of metastases, lobar distribution of metastases, diagnostic interval, type of liver resection, resection margin, perioperative blood transfusion and preoperative carcinoembryonic antigen (CEA) level. Results: 3-year- and 5-year survival was 54% and 33%, median survival was 37 months. The 30 day mortality rate was 0%, postoperative complications occurred in 8 patients (20%). As single factors the following significantly affected the prognosis: number of metastases (p=0.0001), mesenteric lymphnode involvement of the primary tumor (p=0.002), lobar distribution (p=0.002) and intraoperative units of blood (p=0.05). Multivariate analysis revealed that age, gender, mesenteric lymphnode involvement, number of metastases and synchronous versus metachronous metastatic disease were independent predictors of survival. Conclusions: Liver resection is effective in selected patients with hepatic metastases from colorectal cancer. In resectable patients it is not possible to establish a clear prognosis based on the investigated factors. Therefore, patients with adverse prognostic factors should not be denied resection.      

Major hepatectomy in patients with synchronous colorectal liver metastases: whether or not a contraindication to simultaneous colorectal and liver resection?

OBJECTIVE: Synchronous hepatic lesions account for 15-25% of newly diagnosed colorectal cancer and its optimal timing to surgery is not completely defined, but simultaneous colorectal and liver resection is recently gaining acceptance, at least in patients with a right colonic primary and liver metastases that need a minor hepatectomy to be fully resected. METHOD: From September 2002 to December 2004, 16 patients underwent simultaneous resection as treatment of synchronous colorectal liver resection; in 10 patients (62.5%) a major hepatectomy was performed. RESULTS: The mean duration of intervention was 322.5 +/- 59.5 min, operative mortality and morbidity rates was 0% and 25% respectively; the hospitalization was 14.4 (range 8-60) days on average. Mean follow-up was 14 months and actuarial survival was 76.5% at 1 year and 63.5% at 2 years. CONCLUSION: We concluded that simultaneous colonic and liver resection should be undertaken in selected patients with synchronous colorectal liver resection regardless of the extent of hepatectomy; major liver resection, in fact, seems capable of providing better oncological results, allowing resection of liver micrometastases that, in almost one-third of the patients, are located in the same liver lobe of macroscopic lesions, without increased morbidity rates.     

Validity of observation interval for synchronous hepatic metastases of colorectal cancer: changes in hepatic and extrahepatic metastatic foci

Background In cases of synchronous colorectal hepatic metastases, the primary colorectal cancer maintains a strong influence on the metastases, so the possibility of occult hepatic and extrahepatic metastases must be kept in mind. Our treatment policy has been to reevaluate the metastases at an interval of 3 months after colorectal resection and determine treatment strategy. We examined the validity of observation interval for synchronous hepatic metastases. Materials and methods The treatment course was investigated for 36 patients with no extrahepatic lesion remnants at colorectal surgery and a simultaneously resectable liver (H1 group). Results In the H1 group, eight patients underwent simultaneous colorectal and hepatic resections, while the treatment course for 28 patients was decided after an interval. Hepatic resection was not indicated in nine of the 28 patients during the interval. New lesions appeared during the interval in seven of 19 interval hepatic resection patients. In 16 (57%) of 28 interval patients, there was a change in the hepatic resection procedure or surgical indications. Conclusion Reevaluation after an observation interval allows accurate understanding of the number and location of hepatic metastases and is beneficial in determining candidates for surgery and in selecting treatment plan.     

Liver regeneration stimulates tumor metastases

BACKGROUND: Partial hepatectomy for patients with colorectal liver metastases is associated with a tumor recurrence rate approaching 80% post-resection. Different factors and phases associated with regeneration of the liver are implicated in tumor recurrence. This study investigates the effects of the early and late phases of liver regeneration and the impact of the degree of liver resection on stimulating tumor growth and metastasis. MATERIALS AND METHODS: Groups of mice underwent partial hepatectomy (37% or 70%) and were then challenged with colorectal liver carcinoma (CRC) tumors immediately after liver resection (early and late phase effect) or 6 days post liver resection (late phase effect). Tumor growth, degree of proliferation, tumor morphology, and the presence of extrahepatic metastases were investigated 21 days post-tumor induction. RESULTS: The late phase of liver regeneration plays a significant role in tumor stimulation and metastasis. The degree of hepatectomy also appears to be an important factor. The degree of hepatic resection significantly influences tumor growth and the extent of extrahepatic metastases, particularly in the lungs. CONCLUSIONS: Elucidation of the processes involved in the late phase of liver regeneration may assist in the development and timing of adjuvant agents to minimize tumor recurrence during this phase.     

Can the National Health Service Cancer Plan time-line be applied to colorectal hepatic metastases?

INTRODUCTION

The National Health Service (NHS) Cancer Plan guidelines recommend a maximum 2-week wait from referral to first appointment, and 2 months from referral to treatment for primary cancers. However, there are currently no guidelines available for metastatic disease. In the UK, nearly half of all colorectal cancer patients develop hepatic metastases. Timely, surgical resection offers the potential for cure. The aim of this study was to audit current practice for colorectal liver metastases in a regional hepatobiliary unit, and compare this to the NHS Cancer Plan standards for primary disease.

PATIENTS AND METHODS

A retrospective review of the unit''s database was performed for all hepatic metastases referrals from January 2006 to December 2008. The dates of referral, first appointment, investigations and initiation of treatment, along with patient''s age and sex, were recorded on Microsoft Excel and analysed. Time was expressed as mean ± SD in days.

RESULTS

A total of 102 patients with hepatic metastases were identified. Five were excluded due to incomplete data. The average time from referral to first appointment was 10.6 ± 9.4 days and the average time from referral to treatment was 38.5 ± 28.6 days. Seventy-five (72.7%) had surgical intervention, of whom 37 also had chemotherapy.

CONCLUSIONS

The data compare favourably to the NHS Cancer Plan guidelines for primary malignancy, demonstrating that a regional hepatobiliary unit is capable of delivering a service for colorectal liver metastases that adheres to the NHS Cancer Plan. Therefore, the NHS Cancer Plan can be applied to this cohort.     

Repeat hepatic resection as effective treatment for recurrent colorectal liver metastases

Background: Approximately 20–40% of patients who undergo liver resection for colorectal metastases develop recurrent disease confined to the liver. The goals of this study were to determine whether the survival benefit of repeat hepatic resection justified the potential morbidity and mortality. Methods: A retrospective review was performed on all patients who underwent liver resection for colorectal cancer metastases between 1983 and 1995 (N=202). Repeat liver resections were performed on 23 patients for recurrent metastases. Results: There were no operative deaths in the 23 patients, and the postoperative morbidity rate was 22%. The 5-year actuarial survival rate after repeat resection was 32%, with a median length of survival of 39.9 months. There were three patients who survived for >5 years after repeat resection. Sixteen patients (70%) developed recurrent disease at a median interval of 11 months after the second resection; 10 of these 16 patients (62%) had new hepatic metastases. No clinical or pathological factors were significant in predicting long-term survival. Conclusions: Repeat liver resection for recurrent colorectal metastases (a) can be performed safely with acceptable mortality and morbidity rates and (b) may result in long-term survival in some patients.Presented at the 49th Annual Cancer Symposium of The Society of Surgical Oncology, Atlanta, Georgia, March 21–24, 1996.     

HbsAg与结、直肠癌肝转移的关系

目的:探讨HbsAg与结、直肠癌肝转移的关系 。方法:回顾分析582例结、直肠癌病例,对术前HbsAg进行测定,观察它们与肝转移的关系 。结果:发现HbsAg（+）结、直肠癌病例的同时肝转移率为8.9％、异时肝转移率9.4％,HbsAg（-）病例的同时肝转移率为21.1％、异时肝转移率26.3％,HbsAg（+）结、直肠癌的同时肝转移率、异时肝转移率均明显低于HbsAg（-）的病例(P<0.05） 。结论:结、直肠癌较少转移至感染乙肝的肝脏,非感染乙肝的肝转移机率较大。     

Validation of bioluminescence imaging of colorectal liver metastases in the mouse

BACKGROUND: In mouse models for metastatic growth of colorectal carcinoma (CRC) cells in the liver, tumor growth is routinely measured by determining the area of liver tissue that has been replaced by tumor tissue (hepatic replacement area [HRA]). This technique has several major disadvantages. Modern visualization techniques make it possible to image tumor growth noninvasively. In the present report, we validated bioluminescence imaging of liver metastases by comparing it to standard HRA measurements and liver weight. MATERIALS AND METHODS: BALB/c mice received an intrasplenic injection of luciferase-expressing C26 CRC cells and the spleen was subsequently removed. On days 5, 7, 9, and 11 after injection, luciferase activity was measured. After imaging, the mice were sacrificed and the livers was removed, weighed, and fixed. HRA was determined by analyzing liver tissue sections. Comparative trend analyses between luciferase activity, wet liver weight, and HRA were then performed. RESULTS: Luciferase activity, wet liver weight, and HRA all increased over time. Statistical analyses showed that all three types of measurements display a highly significant degree of correlation. CONCLUSIONS: The measurement of tumor growth in the liver by imaging luciferase activity correlates well with the standard method of determining the HRA and with the increase in liver weight that results from tumor growth. Given the great advantages of measuring luciferase activity over measuring HRA, we conclude that bioluminescent imaging is a reliable and superior method for measuring experimental CRC growth in the liver.     

Repeat hepatic cryotherapy for metastatic colorectal cancer

This study evaluated the risks and benefits of repeat hepatic cryotherapy for recurrent, unresectable hepatic metastases from colorectal carcinoma. Review of a prospective database identified 195 patients who underwent hepatic cryotherapy for metastatic colorectal carcinoma during a 7-year period. Of the 14 patients who underwent successful repeat cryotherapy for recurrences confined to the liver, 86% had Duke’s stage D colorectal carcinoma at initial diagnosis. The median age of the 14 patients was 58 years (range 41 to 77 years). The median number of hepatic metastases was three at the first cryotherapy and two at the second cryotherapy. At a median follow-up of 71 months, the mean survival times from original diagnosis, first cryotherapy, and second cryotherapy were 53,42, and 19 months, respectively. At the most recent follow-up, eight patients (57%) have died of their disease, four (29%) are alive with disease, and two (14%) have no evidence of disease. The mean interval between the first and second cryotherapies was 23 months. The complication rates after the first and second cryotherapies were 7% and 14%, respectively. One patient developed a wound dehiscence after the first cryotherapy. Following the second cryotherapy, one patient had a small bowel obstruction and another had a pleural effusion. There was no perioperative mortality. Repeat cryotherapy for recurrent, unresectable hepadc metastases from colorectal cancer is safe and improves survival. However, a prospective trial is needed to validate the efficacy of systemic therapy and to better define the indications for repeat hepatic cryotherapy. Supported in part by grant T32 CA 09689 from the National Cancer Institute and by funding from the Rogovin-Davidow Foundation, Los Angeles, Calif. Presented at the Forty-First Annual Meeting of The Society for Surgery of the Alimentary Tract, San Diego, Calif., May 2l–24, 2000.     

Changes in the microvascular architecture of colorectal liver metastases following the administration of SMANCS/lipiodol

BACKGROUND: Liver metastases are the major cause of death for patients with colorectal cancer. Surgical resection is at present the only curative option. Styrene maleic acid neocarzinostatin [SMANCS/Lipiodol (S/L)] targets the unique vascular architecture of tumor blood vessels, which are hyperpermeable and lack a well-developed lymphatic system. Here we report changes in the microvascular architecture of liver metastases by scanning electron microscopy (SEM) following the administration of S/L. MATERIALS AND METHODS: Liver metastases were induced by the intrasplenic injection of dimethylhydrazine induced colon cancer cells in mice. In this model tumor angiogenesis occurs at day 10, while exponential tumor growth occurs at day 16. Changes in the tumor microvasculature were observed at 3 weeks following treatment with S/L at these time points by SEM of corrosion casts. RESULTS: Tumors treated with S/L at day 10 appear similar to day 10 controls. Tumor vessels, 50 +/- 18 microm in diameter, are easily identified from hepatic vessels. Within the hepatic sinusoids are avascular spaces, 144 +/- 60 microm in diameter, which correspond to tumor cell aggregates at the initial stages of growth. Similarly, day 16 treated tumors appear comparable to day 16 controls. These vessels are narrower (84 +/- 32 microm vs. 150 +/- 70 microm) than their control counterparts. This is in contrast to vessels (216 +/- 36 microm in diameter) of a complex nature at 3 weeks. CONCLUSIONS: S/L exerts a marked and immediate effect on the tumor microvessels at both the angiogenic and the exponential phases of tumor growth. This agent is effective at the microvascular level during inhibition of metastatic growth.