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Biomedical subjects

A R Moossa

Publications and source records attributed to A R Moossa.

At least 199 records · Page 11Linked to original sources
PubMedDate not supplied

A nude mouse model of massive liver and lymph node metastasis of human colon cancer.

Liver and lymph nodes metastasis are the main causes of treatment failure for advanced colon cancer. However, currently-available animal models of human colon cancer do not demonstrate sufficient metastasis to represent highly malignant colon cancer that extensively metastasizes to these sites. A liver metastasis from a patient with highly malignant, poorly differentiated adenocarcinoma of the colon was established in nude mice by surgical orthotopic implantation to the mouse colon. The human origin of the tumor growing in nude mice was confirmed by in situ hybridization of human DNA. After 20 passages from the first implantation, massive liver and lymph nodes metastasis, occurred in 100% of the transplanted animals. Lymph nodes metastasis were found at the sites of lymph node drainage of the liver: celiac, portal and mediastinal lymph nodes. However no mesenteric and retroperitoneal nodes or lung tissue metastases were observed. Our data suggest that the mediastinal, celiac and hepatic lymph nodes metastases are derived form the liver metastasis, confirming the concept of metastasis of metastases or "remetastasis" of colon cancer.

Adenocarcinoma↗
PubMedDate not supplied

Cisplatin sensitivity of ovarian cancer in the histoculture drug response assay correlates to clinical response to combination chemotherapy with cisplatin, doxorubicin and cyclophosphamide.

The histoculture drug sensitivity assay (HDRA) has been demonstrated to have high predictability for resistance, sensitivity, and survival for gastrointestinal cancer (Clin Cancer Res 1: 305-311, 1995; Clin Cancer Res 1: 1537-1543, 1995). In this report, we evaluated the clinical usefulness of the HDRA in ovarian cancer. HDRA was performed on tumors from patients with ovarian cancer. Eighty-five cases (97%) were evaluable. Tumor fragments were cultured on collagen-sponge gels. The cultures were incubated with cisplatin (CDDP) for seven days. Cell viability were assessed with the MTT end point. The optimal cut off concentration of CDDP was determined to be 25 micrograms/ml by correlation with the historical clinical response rate to CDDP. HDRA results were correlated to clinical response of 15 patients who received CDDP-based therapy that included doxorubicin and cyclophosphamide (CAP therapy). The true positive rate was 88%, the true negative rate was 86%, the sensitivity was 88%, the specificity was 86%, and the accurate prediction rate was 87% when HDRA results were compared to the response of the treated patients. The data suggest that the HDRA is capable of predicting the response to antitumor chemotherapy in patients with ovarian cancer and that measuring response to CDDP can be useful for optimization of CAP chemotherapy for patients with this disease.

Adenocarcinoma, Clear Cell↗
PubMedDate not supplied

Combination efficacy of doxorubicin and adenoviral methioninase gene therapy with prodrug selenomethionine.

We have previously demonstrated an enzyme activation prodrug gene therapy strategy using the methionine alpha,gamma-lyase gene (MET) cloned from Pseudomonas putida, in combination with selenomethionine (SeMET) as a prodrug. MET gene transfer via a recombinant adenovirus (Ad-MET) converts the physiologic compound SeMET to highly toxic methylselenol. In this study, we have developed a combination therapy approach using Ad-MET/SeMET gene therapy and doxorubicin (DOX). The combination significantly delayed the growth of H460, an aggressively-growing human lung cancer cell line, in nude mice. H460 cells were injected intra-dermally in nude mice. Tumor-bearing mice were divided into 12 groups [Control (Ctrl), DOX, SeMET, SeMET + DOX, Ad-Ctrl, Ad-Ctrl + SeMET, Ad-Ctrl + DOX, Ad-Ctrl + SeMET + DOX, Ad-MET, Ad-MET + DOX, Ad-MET + SeMET, and Ad-MET + SeMET + DOX]. DOX (2 mg/kg body weight) was given intra-peritoneally twice at 7-day intervals. SeMET (1 microM/mouse) was given by intra-tumor injection everyday, starting the following day after transfection with adenovirus. Tumor growth in the untreated group showed a 10-fold increase in tumor volume after two weeks. In contrast, the increase was only 2.5-fold in the DOX + Ad-MET/SeMET group. The treatment with DOX alone at the low-dose used showed no effect compared to the control group. There was a 5.8-fold increase in tumor volume in mice treated with Ad-MET/SeMET gene therapy alone. The tumor doubling-time was increased to approximately 10 days with the combination therapy of Ad-MET + SeMET + DOX as opposed to 2-3 days in all other treatment groups.

Animals↗
PubMedDate not supplied

Non-pancreatic periampullary adenocarcinomas: an explanation for favorable prognosis.

BACKGROUND/AIMS: Our previous studies demonstrate that patients with non-pancreatic periampullary adenocarcinomas have a favorable prognosis relative to those with pancreatic adenocarcinoma. This study investigates histopathologic factors that contribute to the superior outcome of these patients. METHODOLOGY: A retrospective review of all patients explored for periampullary neoplasms at a single institution over a 20-year period. RESULTS: 291 patients with periampullary neoplasms underwent exploratory laparotomy, of which 185 had resectable tumors. Periampullary adenocarcinomas were resected in 120: pancreatic head (n=74), distal common bile duct (n=10), duodenum (n=5), and ampulla of Vater (n=31). The resection rate for non-pancreatic adenocarcinomas was 90%, while that of pancreatic cancers was 44% (p<0.01). Median survival for resected non-pancreatic adenocarcinomas was 38.8 months; that of pancreatic tumors was 15.3 months (p<0.01). Non-pancreatic adenocarcinomas were significantly smaller (p<0.001), better differentiated (p<0.001), and less likely to have involved nodes (p<0.001), margins (p<0.001), perineural invasion (p<0.001), or vascular invasion (p<0.2) than pancreatic adenocarcinomas. CONCLUSIONS: Histopathologic features of non-pancreatic periampullary adenocarcinomas significantly differentiate them from pancreatic adenocarcinoma and contribute to their relatively favorable long-term outcome following resection.

Adenocarcinoma↗
PubMedDate not supplied

Color coding cancer cells with fluorescent proteins to visualize in vivo cellular interaction in metastatic colonies.

We report here in vivo visualization of cancer cell interaction using stable sublines of green fluorescent protein (GFP)- and red fluorescent protein (RFP)-expressing HT-1080 human fibrosarcoma cells. These color-coded fibrosarcoma cell lines show similar cell proliferation and lung metastasis potential. The color-coded cells were mixed at a ratio of 1:1 and were injected into the tail vein of severe combined immunodeficient (SCID) mice. The resulting experimental lung metastases were simultaneously imaged and their ratio was determined by color-pixel analysis. Fluorescence color coding of cancer cells enables visualization of the interaction of cancer cells and can be used to distinguish cancer cells of any genotype or phenotype.

Animals↗
PubMedDate not supplied

Dual-color imaging of nascent angiogenesis and its inhibition in liver metastases of pancreatic cancer.

As previously shown, the stem cell marker nestin is expressed in nascent blood vessels in transgenic nestin-driven green fluorescent protein (ND-GFP) nude mice. This mouse model was recently utilized to evaluate angiogenesis in primary tumors in an orthotopic model of pancreatic cancer. In the present study, nascent angiogenesis of pancreatic cancer liver metastasis in the ND-GFP transgenic nude mice after splenic injection of low-passage xPA-1 human pancreatic cancer cells expressing red fluorescent protein (RFP) was visualized by dual-color fluorescence imaging. ND-GFP was highly expressed in proliferating endothelial cells and nascent blood vessels in the growing liver metastasis. Immunohistochemical staining showed that CD31 co-localized in ND-GFP-expressing nascent blood vessels. The density of nascent blood vessels in the tumor was readily quantitated. Gemcitabine significantly decreased the mean nascent blood vessel density in the pancreatic liver metastases. In conclusion, the dual-color model of the ND-GFP nude mouse with RFP-expressing pancreatic cancer liver metastases, enabled the simultaneous visualization and quantitation of nascent angiogenesis and its response to angiogenesis inhibitors. This model will be useful for understanding the mechanism of angiogenesis of pancreatic cancer liver metastasis and for the discovery of effective new inhibitors of this process.

Animals↗
PubMedDate not supplied

"Seed" to "soil" is a return trip in metastasis.

A critical aspect in understanding and treating cancer progression and metastasis is the relationship of the host originating organ and metastatic "soil" organs that support the growth and progression of the cancer "seed". We have recently demonstrated that there is a great difference in seemingly similar visceral organs, the colon and the stomach to support the growth progression of transplanted human colon tumors in nude mice. To further understand the relationship of seed and soil in cancer, we transplanted the metastatic human colon tumor CO-3 on the liver of nude mice, which is a usual metastatic soil organ for this tumor if transplanted to the nude-mouse colon. The intrahepatically-transplanted CO-3 tumor grew extensively on the nude-mouse liver without intra-hepatic metastasis. However, cecal growth, peritoneal dissemination, and invasiveness were noted after extensive growth on the liver with no spread to other organs. This phenomenon suggested that the intra-hepatically transplanted tumor could "reversibly metastasize" to the orthotopic site and secondarily spread into the abdominal cavity. The observation reported here suggests that "seed" to "soil" is reversible in metastasis in that the tumor can spread in either direction between two "matched" organ "soil".

Adenocarcinoma↗
PubMedDate not supplied

Cancer seed and soil can be highly selective: human-patient colon tumor lung metastasis grows in nude mouse lung but not colon or subcutis.

The question remains as to whether metastatic cells (cancer seed) that eventually colonize a particular organ (cancer soil) have specific properties that distinguish them from the other cells of the primary tumor. However until recently there have not been model systems in which this question could be fully answered. To further understand the relationship between seed and soil we have developed an orthotopic-transplantation nude-mouse model that allows human tumors to essentially replicate their behavior they had in the patient. The patient-like behavior of the transplanted human tumor in the nude mouse depends on the use of intact tumor tissue for orthotopic transplantation. Here we report that a colorectal tumor lung metastasis surgically resected from a patient could grow in nude mouse lung, but not in either the colon or the subcutis after transplantation of intact tissue. The results were striking in that the human colorectal tumor lung metastasis grew in the lung of the animals and not in the colon or in the subcutis of the animals. The results described here suggest that the lung metastasis of the patient colon tumor is distinct in its soil requirement from the majority of the cells of the original colon tumor. In contract, in the intact-tissue orthotopic transplant model, primary human colon tumors grow when transplanted to the colon of the nude mouse. Thus the colorectal cancer "seed" which metastasized to the lung in the patients seems very selective for the "soil" of the lung of both the patient and the nude mouse.

Animals↗
PubMedDate not supplied

A clinical nude mouse metastatic model for highly malignant human pancreatic cancer.

Pancreatic cancer is a highly aggressive and treatment-refractory cancer. A clinically-relevant animal model is necessary to develop therapy for metastatic pancreatic cancer. In this study we evaluated the efficacy of mitomycin C (MMC) and 5-FU against the human pancreatic adenocarcinoma cell line PAN-12 in an orthotopic human metastatic pancreatic cancer nude mice model. The model is constructed by surgical orthotopic implantation (SOI) of histologically intact tumor tissue in the tail portion of the pancreas near the spleen. PAN-12 grew very aggressively in the control group of nude mice with extensive local invasion and distant metastasis to various organs with a propensity for the lung but to other organs as well, including the liver, kidney and regional and distant lymph nodes. In a striking effect none of the mice in the MMC-treated group developed tumor. Although mice in the 5-FU treated group survived statistically significantly longer than those in the untreated control, the overall incidence of metastasis in these mice was equivalent to those in the control. However no liver or kidney metastases were found in the 5-FU treated animals perhaps accounting in part for their longer survival. This "clinical" nude mouse model of highly metastatic pancreatic cancer can now be used to discover new effective agents for this disease.

Adenocarcinoma↗
PubMedDate not supplied

Interferon gamma is highly effective against orthotopically-implanted human pleural adenocarcinoma in nude mice.

The efficacy of recombinant human gamma interferon (rh IFN-gamma) was evaluated for the treatment of human pleural adenocarcinoma in a patient-like nude mice model which is constructed by surgical orthotopic implantation (SOI) of histologically-intact human tumor tissue. The human non-small-cell lung cancer cell line H-460 was used for the study. Gamma interferon was tested in three different dosages (25,000 U, 50,000 U and 100,000 U) versus an untreated control through i.p. injection twice a day for five days, which was started 48 hours after SOI; The results showed that IFN-gamma can prolong the survival time of the tumor-bearing animals. The symptoms and signs of hypoxia such as restricted physical activity and cyanosis due to primary tumor growth in the thoracic cavity as well as cachexia developed much earlier in the control than in the IFN-gamma-treated mice. The mice in the control group had succumbed by day-23 after tumor implantation, however at that time 67% of the mice in the 100,000 U-treated group, 15% of the mice in the 50,000 U-treated group, and 16% of the mice in the 25,000 U-treated group were still alive. The orthotopically-transplanted tumor grew rapidly and metastasized to the lung and liver in the untreated control. In the IFN-gamma-treated groups both primary tumor growth and metastasis were reduced, probably accounting for the increased survival rate. The results demonstrated dose-dependent efficacy of IFN-gamma in suppressing symptomology, primary tumor growth, invasiveness and metastasis of the human lung cancer cell line H 460, and increased survival of the tumor-bearing animals. These results suggest clinical trials of IFN-gamma should begin for treatment of pleural adenocarcinoma for which there is no current effective therapy.

Adenocarcinoma↗
PubMedDate not supplied

Methionine depletion modulates the antitumor and antimetastatic efficacy of ethionine.

The elevated methionine requirement for the growth of tumors, termed methionine dependence, is a potentially highly effective therapeutic target. To attack this target we are developing anti-methionine chemotherapy. In this study of anti-methionine chemotherapy we have observed that the methionine analog ethionine is synergistic with methionine depletion in arresting the growth of the Yoshida sarcoma both in vitro and when transplanted to nude mice. In contrast, ethionine in vitro in a methionine-containing medium is not effective against Yoshida sarcoma cells. Similarly, ethionine administered along with a methionine-containing diet is ineffective against the Yoshida sarcoma growing in nude mice. A methionine-depleted diet alone is only partially effective against tumor growth. The Yoshida sarcoma gave rise to metastases in 75% of the- organs observed in the mice on the methionine-containing diet, and 43 % of the organs in the mice on the methionine-free diet. In striking contrast, no metastases were observed in the ethionine-treated animals on the methionine-free diet. Anti-methionine chemotherapy consisting of dietary methionine depletion and ethionine administration caused an initial weight loss but the animals weight stabilized resulting in no animal deaths. The synergism of ethionine and methionine depletion is markedly similar in vitro and in vivo suggesting the observed efficacy is due to the specific anti-methionine targeting. Thus methionine depletion highly potentiates the anti-tumor and anti-metastatic effectiveness of ethionine suggesting that anti-methionine chemotherapy consisting of methionine depletion as a modulator of methionine analogs holds great promise as a new, tumor-selective therapeutic approach.

Animals↗