Kenneth Pienta | Johns Hopkins University (original) (raw)

Papers by Kenneth Pienta

Oncotarget, Jan 8, 2015

Resident macrophages in bone play important roles in bone remodeling, repair, and hematopoietic s... more Resident macrophages in bone play important roles in bone remodeling, repair, and hematopoietic stem cell maintenance, yet their role in skeletal metastasis remains under investigated. The purpose of this study was to determine the role of macrophages in prostate cancer skeletal metastasis, using two in vivo mouse models of conditional macrophage depletion. RM-1 syngeneic tumor growth was analyzed in an inducible macrophage (CSF-1 receptor positive cells) ablation model (MAFIA mice). There was a significant reduction in tumor growth in the tibiae of macrophage-ablated mice, compared with control non-ablated mice. Similar results were observed when macrophage ablation was performed using liposome-encapsulated clodronate and human PC-3 prostate cancer cells where tumor-bearing long bones had increased numbers of tumor associated-macrophages. Although tumors were consistently smaller in macrophage-depleted mice, paradoxical results of macrophage depletion on bone were observed. Histomo...

Handbook of Dietary Fiber, 2001

PloS one, 2015

ClinicalTrials.gov NCT02064283.

Anticancer research

The etiology of prostate cancer is currently a mystery. Several epidemiological studies suggest a... more The etiology of prostate cancer is currently a mystery. Several epidemiological studies suggest a link between dietary fat and prostate cancer. In vitro and in vivo studies support this evidence. Using the Dunning model of rat prostate cancer we hypothesized that a high-fat diet (20%) would increase the growth of the R3327-H tumor. R3327-H tumors were implanted subcutaneously into male Copenhagen rats which were fed diets with 5 or 20% total fat. Tumors were allowed to grow for 16 weeks; they were then excised and weighed. The initial and final weights of the rats were also recorded. Statistical analysis revealed the level of dietary fat was a positive predictor of weight gain (p < 0.01). No effect on tumor growth was seen when compared to dietary fat, fiber type, or the interaction of fat and fiber. Growth of the R3327-H tumor, when implanted subcutaneously, is not affected by the level of dietary fat.

Cancer research, Jan 15, 1993

The progression from normal breast epithelium to a malignant phenotype may depend on changes in g... more The progression from normal breast epithelium to a malignant phenotype may depend on changes in genetic events as well as failure of host mechanisms. Intermediate biomarkers are needed to more effectively identify malignant progression as well as to develop the potential for more specific treatments and prevention strategies. The nuclear matrix is the RNA-protein network which forms the skeleton of the nucleus and participates in DNA organization as well as multiple cellular functions. Nuclear matrix proteins have been demonstrated to be tissue and cell type specific as well as to reflect the state of cell differentiation and/or transformation. We prepared nuclear matrices from normal and cancer breast tissue from 10 patients with infiltrating ductal carcinoma of the breast as well as the MCF-10 mortal, immortal, and transfected breast cell lines. Nuclear matrices derived from normal human breast tissue and tumor tissue share common nuclear matrix proteins as well as demonstrate spe...

International journal of oncology, 1994

Angiogenesis in early stage breast cancer has been suggested to be an independent prognostic fact... more Angiogenesis in early stage breast cancer has been suggested to be an independent prognostic factor for metastasis and overall survival. We retrospectively studied 316 cases of early breast cancer with a mean follow-up period of 94 months to determine the role of angiogenesis as a prognostic factor in breast cancer utilizing a Factor VIII immuno-histochemical assay. In a univariate analysis, patients with microvessel counts in the lower 25th percentile had significantly better overall disease-free survival than patients in the upper quartiles (p<0.017). In a multivariate analysis of disease-free survival, microvessel counts did not add to prognostic information when controlling for estrogen receptor status and lymph node status, but did add prognostic information when controlling for tumor size.

Anticancer research

The case of a 66-year-old gentleman who presented with unilateral proptosis, eye pain and partial... more The case of a 66-year-old gentleman who presented with unilateral proptosis, eye pain and partial loss of vision seven years after his original prostate cancer diagnosis is reported. MRI of the orbits revealed a 2-cm lesion in the posterolateral right orbital wall near the optic foramen with compression of the optic nerve. Metastatic orbital lesions are relatively uncommon in prostate cancer. Treatment is palliative and varies according to the time of presentation in the course of the disease. This patient's symptoms resolved after reinitiation of combined androgen blockade.

Anticancer research

Previous studies have reported that tumor cells' adhesion to quiescent endothelial cell is me... more Previous studies have reported that tumor cells' adhesion to quiescent endothelial cell is mediated by beta-1 integrins. The aim of this study was to determine the role beta-1 integrins play in prostate cancer cell adhesion to human bone marrow endothelial cells (HBME) and human aortic endothelial cells (HAEC). A well described blocking antibody to beta-1 integrin subunit was used in adhesion assays to determine the role of beta-1 integrin subunit in the adhesion of PC-3 cells to both HBME cells and HAEC. Antibody to the beta-1 integrin subunit failed to reduce PC-3 adhesion to HBME and HAEC, yet this same antibody significantly reduced adhesion of PC-3 cells to fibronectin coated wells. The data suggest that metastasis of prostate cancer cells to bone may be mediated, in part, by preferential adhesion to HBME cells; but beta-1 integrins most likely are not involved in this interaction.

International journal of oncology, 2000

Recent studies have provided convincing evidence for the role of soy-isoflavones, particularly ge... more Recent studies have provided convincing evidence for the role of soy-isoflavones, particularly genistein, in the inhibition of prostate cancer cell growth. Prostate specific antigen (PSA) is a biological marker used to detect and monitor the treatment of prostate cancer patients. Previous studies have documented that isoflavones can inhibit the secretion of PSA in the androgen-dependent prostate cancer cell line, LNCaP, however, the effects of genistein on androgen-independent PSA expression has not been explored. In this study, we have utilized a prostate cancer cell line, VeCaP, which expresses PSA in an androgen-independent manner, to determine the effects of genistein on cell proliferation and PSA expression. Here we show that genistein inhibits cell growth similarly in both the LNCaP and VeCaP cell lines, but has differential effects on PSA expression. We demonstrate using concentrations of genistein that have been detected in the serum of humans consuming a soy-rich diet, that...

Anticancer research

Gemcitabine has demonstrated clinical activity against several common cancers. Our studies examin... more Gemcitabine has demonstrated clinical activity against several common cancers. Our studies examine the ability of gemcitabine, both alone and in combination with other chemotherapeutic agents, to inhibit the in vitro and in vivo growth of several prostate cancer cell lines. Cultures of LNCaP, PC-3 or MLL cells were exposed to either gemcitabine or other appropriate agents for specified amounts of time. Cells were lysed and nuclei counted utilizing a Coulter Counter. For in vivo experiments, animals were injected with 1 x 10(5) MLL cells subcutaneously into the right flank. Animals were treated as indicated for 14 days. Tumors were then excised, weighed and measured. In both human (PC-3 and LNCaP) and rat prostate (MLL) cancer cell lines our studies demonstrated gemcitabine had a strong effect in vitro, with an IC50 of approximately 500 nM in the human lines and 10 nM in MLL cells. In vivo, studies using the Dunning prostate cancer model in Copenhagen rats resulted in a dose response...

Clinical cancer research : an official journal of the American Association for Cancer Research, 2000

In this report, we describe the distribution of metastases from 14 patients who had hormone-refra... more In this report, we describe the distribution of metastases from 14 patients who had hormone-refractory adenocarcinoma of the prostate and agreed while alive to undergo directed autopsies after their deaths. These autopsies were undertaken specifically to document the distribution of metastases, characterize tumors phenotypically and immunohistochemically, harvest fresh and snap frozen tumor and normal control tissues suitable for molecular examination, and establish cell lines via passages through generations of severe combined immunodeficient and athymic mice. Achievement of these goals was obtained through the development of a multidisciplinary team approach. Team members included a medical oncologist, pathologists, urologists, and researchers. The autopsy and tissue procurement teams were available on a round-the-clock basis. The tissues harvested from these autopsies yielded high-quality tumor samples, as evidenced by excellent preservation seen by light microscopy, strong prost...

Cancer research, Jan 15, 2000

Using naturally serum-free SU-ECM basement membranes as invasion substrates showed that plasma fi... more Using naturally serum-free SU-ECM basement membranes as invasion substrates showed that plasma fibronectin was necessary to stimulate invasion by DU 145 human and metastatic MATLyLu (MLL) rat prostate carcinoma cells. This activity mapped to the PHSRN sequence, which induced invasion through alpha5beta1 integrin. PHSCN, a competitive inhibitor, blocked both PHSRN- and serum-induced invasion. Acetylated, amidated PHSCN (Ac-PHSCN-NH2) was 30-fold more potent; however, Ac-HSPNC-NH2 was inactive. Rats receiving injections s.c. with 100,000 MLL cells were treated systemically by i.v. injection three times weekly with 1 mg of either Ac-PHSCN-NH2 or Ac-HSPNC-NH2 beginning 24 h later, three times weekly with 1 mg of Ac-PHSCN-NH2 beginning only after surgery to remove large (2 cm) MLL tumors, or were left untreated. MLL tumors grew rapidly in Ac-HSPNC-NH2-treated and in untreated rats. MLL tumor growth in rats treated with Ac-PHSCN-NH2 beginning 1 day after MLL cell injection was reduced by ...

Clinical cancer research : an official journal of the American Association for Cancer Research, 2000

Preclinical and in vitro studies have determined that copper is an important cofactor for angioge... more Preclinical and in vitro studies have determined that copper is an important cofactor for angiogenesis. Tetrathiomolybdate (TM) was developed as an effective anticopper therapy for the initial treatment of Wilson's disease, an autosomal recessive disorder that leads to abnormal copper accumulation. Given the potency and uniqueness of the anticopper action of TM and its lack of toxicity, we hypothesized that TM would be a suitable agent to achieve and maintain mild copper deficiency to impair neovascularization in metastatic solid tumors. Following preclinical work that showed efficacy for this anticopper approach in mouse tumor models, we carried out a Phase I clinical trial in 18 patients with metastatic cancer who were enrolled at three dose levels of oral TM (90, 105, and 120 mg/day) administered in six divided doses with and in-between meals. Serum ceruloplasmin (Cp) was used as a surrogate marker for total body copper. Because anemia is the first clinical sign of copper def...

Anticancer research

Most deaths from prostate cancer result from the metastatic spread of the disease. Castanospermin... more Most deaths from prostate cancer result from the metastatic spread of the disease. Castanospermine has been shown to inhibit tumor growth and metastasis in mouse and rat models. We hypothesized that castanospermine might inhibit metastasis in the Dunning model of rat prostate adenocarcinoma by interfering with the metastatic properties of tumor cells. We examined the cytotoxicity of castanospermine toward the metastatic MAT-LyLu and nonmetastatic AT. 1 cell lines and its effects on cell motility and adhesion to endothelial cells. We assessed castanospermine's effects on in vivo metastasis in Copenhagen rats. Castanospermine was not cytotoxic toward the MAT-LyLu and AT. 1 cell lines at concentrations through 10 micrograms/mL, nor did it significantly affect cell motility, adhesion to endothelial cells, or in vivo metastasis. Within the Dunning model, castanospermine did not appear to significantly affect cell characteristics related to metastatic potential.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 1994

Estramustine and etoposide (VP-16) have been demonstrated to inhibit the growth of prostate cance... more Estramustine and etoposide (VP-16) have been demonstrated to inhibit the growth of prostate cancer cells in experimental models. This led us to evaluate the effectiveness of this combination in the treatment of patients with metastatic prostate carcinoma refractory to hormone therapy. Estramustine 15 mg/kg/d and VP-16 50 mg/m2/d, were administered orally in divided doses for 21 days. Patients were then taken off therapy for 7 days and the cycle then repeated. Therapy continued until evidence of disease progression. Forty-two patients have been enrolled onto this trial with a minimum of 40 weeks follow-up. Of 18 patients with measurable soft tissue disease, three demonstrated a complete response (CR) and six a partial response (PR) for longer than 2 months. Of these 18 patients, pretreatment prostate-specific antigen (PSA) levels decreased by at least 75% in five men (28%) and by at least 50% in nine (50%). The median survival duration has not been reached in those patients who demon...

Anticancer research

All solid tumors require the induction of new blood vessels to grow. To begin to study this pheno... more All solid tumors require the induction of new blood vessels to grow. To begin to study this phenomenon in prostate cancer, we investigated the intensity of tumor associated angiogenesis in prostate non malignant and malignant tissue. Angiogenesis was measured by quantitating microvessels in a total of 67 patients: 23 non malignant biopsy specimens, and 34 malignant specimens from patients who had undergone prostatectomy. Angiogenic activity in prostatic cancer (prostatectomy) tissue (utilizing Factor VIII staining) was then correlated with pathological staging (Whitmore-Jewitt). Overall there appeared to be a trend of increasing microvessel count (MVC) from benign through the advancing stages of prostate cancer. Based on mean microvessel counts we were able to distinguish stage D from all other pathological stages (p = 0.004 between stages C and D). There was, however, no statistically significant difference between stage B and C. We conclude that tumor associated angiogenesis in pr...

Anticancer research

Maltose tetrapalmitate (MTP), a non-toxic synthetic glycolipid analog of lipid A, has been shown ... more Maltose tetrapalmitate (MTP), a non-toxic synthetic glycolipid analog of lipid A, has been shown to have antitumor activity in tumor-transplanted animals. Its mode of action has been postulated to be as an immunoadjuvant or as an anti-angiogenesis agent. MTP has been shown to have antitumor properties in lung, bladder, mammary, colon, liver and soft tissue tumors, but its action on prostate cancer has not yet been investigated. The effect of MTP alone and in combination with hydrocortisone hemisuccinate on prostate cancer and the ability of MTP to inhibit angiogenesis were examined in this study. In vitro, MTP was minimally cytotoxic to rat prostate cancer cells and to bovine and human endothelial cells at high concentrations. In the angiogenesis inhibition assays, the MTP alone exhibited no anti-angiogenesis effect and significant anti-angiogenesis activity only when combined with hydrocortisone hemisuccinate at high doses. In vivo, however, MTP demonstrated significant inhibition ...

International Journal of Oncology, 1995

Hormone refractory prostate cancer remains an incurable disease and the discovery of newer agents... more Hormone refractory prostate cancer remains an incurable disease and the discovery of newer agents with higher cytotoxic activity is required. Gossypol is a phenolic compound isolated from cottonseed oil which has been shown to have anti-spermatogenic effects. In in vitro studies, gossypol appears to inhibit the growth of rat prostate cancer cell line MAT-LyLu and human prostate adenocarcinoma cell lines PC-3, LNCaP and DU-145. In vive, gossypol appeared to inhibit tumor growth of subcutaneously implanted MAT-LyLu cells in Copenhagen rats. Gossypol may be an active agent for the treatment of hormone refractory metastatic prostate cancer.

Cancer research, Jan 15, 1989

The present study investigated the in vitro and in vivo antitumor effects of gossypol on human SW... more The present study investigated the in vitro and in vivo antitumor effects of gossypol on human SW-13 adrenocortical carcinoma cells. In vitro gossypol concentrations greater than or equal to 0.5 microM reduced the growth rate of the SW-13 cells. Membrane microviscosity was determined by fluorescence polarization of diphenylhexatriene. The membranes of viable SW-13 cells exposed to gossypol became more rigid after a 1-day exposure to gossypol, the polarization constant, P, increasing from 0.229 to 0.352. Gossypol also increased the microviscosities of isolated mitochondrial and microsomal enriched membrane preparations. Tumor was also transplanted into nude mice by s.c. injection of SW-13 cells. A 1-week pretreatment period followed by daily administration of gossypol in which 30 mg gossypol/kg body weight/day was administered via orogastric tube delayed the onset of visible tumor in the subsequent weeks. Five weeks after transplantation, tumor prevalence rate was 95.8% in the contro...

Critical reviews in eukaryotic gene expression, 1991

Oncotarget, Jan 8, 2015

Resident macrophages in bone play important roles in bone remodeling, repair, and hematopoietic s... more Resident macrophages in bone play important roles in bone remodeling, repair, and hematopoietic stem cell maintenance, yet their role in skeletal metastasis remains under investigated. The purpose of this study was to determine the role of macrophages in prostate cancer skeletal metastasis, using two in vivo mouse models of conditional macrophage depletion. RM-1 syngeneic tumor growth was analyzed in an inducible macrophage (CSF-1 receptor positive cells) ablation model (MAFIA mice). There was a significant reduction in tumor growth in the tibiae of macrophage-ablated mice, compared with control non-ablated mice. Similar results were observed when macrophage ablation was performed using liposome-encapsulated clodronate and human PC-3 prostate cancer cells where tumor-bearing long bones had increased numbers of tumor associated-macrophages. Although tumors were consistently smaller in macrophage-depleted mice, paradoxical results of macrophage depletion on bone were observed. Histomo...

Handbook of Dietary Fiber, 2001

PloS one, 2015

ClinicalTrials.gov NCT02064283.

Anticancer research

The etiology of prostate cancer is currently a mystery. Several epidemiological studies suggest a... more The etiology of prostate cancer is currently a mystery. Several epidemiological studies suggest a link between dietary fat and prostate cancer. In vitro and in vivo studies support this evidence. Using the Dunning model of rat prostate cancer we hypothesized that a high-fat diet (20%) would increase the growth of the R3327-H tumor. R3327-H tumors were implanted subcutaneously into male Copenhagen rats which were fed diets with 5 or 20% total fat. Tumors were allowed to grow for 16 weeks; they were then excised and weighed. The initial and final weights of the rats were also recorded. Statistical analysis revealed the level of dietary fat was a positive predictor of weight gain (p < 0.01). No effect on tumor growth was seen when compared to dietary fat, fiber type, or the interaction of fat and fiber. Growth of the R3327-H tumor, when implanted subcutaneously, is not affected by the level of dietary fat.

Cancer research, Jan 15, 1993

The progression from normal breast epithelium to a malignant phenotype may depend on changes in g... more The progression from normal breast epithelium to a malignant phenotype may depend on changes in genetic events as well as failure of host mechanisms. Intermediate biomarkers are needed to more effectively identify malignant progression as well as to develop the potential for more specific treatments and prevention strategies. The nuclear matrix is the RNA-protein network which forms the skeleton of the nucleus and participates in DNA organization as well as multiple cellular functions. Nuclear matrix proteins have been demonstrated to be tissue and cell type specific as well as to reflect the state of cell differentiation and/or transformation. We prepared nuclear matrices from normal and cancer breast tissue from 10 patients with infiltrating ductal carcinoma of the breast as well as the MCF-10 mortal, immortal, and transfected breast cell lines. Nuclear matrices derived from normal human breast tissue and tumor tissue share common nuclear matrix proteins as well as demonstrate spe...

International journal of oncology, 1994

Angiogenesis in early stage breast cancer has been suggested to be an independent prognostic fact... more Angiogenesis in early stage breast cancer has been suggested to be an independent prognostic factor for metastasis and overall survival. We retrospectively studied 316 cases of early breast cancer with a mean follow-up period of 94 months to determine the role of angiogenesis as a prognostic factor in breast cancer utilizing a Factor VIII immuno-histochemical assay. In a univariate analysis, patients with microvessel counts in the lower 25th percentile had significantly better overall disease-free survival than patients in the upper quartiles (p<0.017). In a multivariate analysis of disease-free survival, microvessel counts did not add to prognostic information when controlling for estrogen receptor status and lymph node status, but did add prognostic information when controlling for tumor size.

Anticancer research

The case of a 66-year-old gentleman who presented with unilateral proptosis, eye pain and partial... more The case of a 66-year-old gentleman who presented with unilateral proptosis, eye pain and partial loss of vision seven years after his original prostate cancer diagnosis is reported. MRI of the orbits revealed a 2-cm lesion in the posterolateral right orbital wall near the optic foramen with compression of the optic nerve. Metastatic orbital lesions are relatively uncommon in prostate cancer. Treatment is palliative and varies according to the time of presentation in the course of the disease. This patient's symptoms resolved after reinitiation of combined androgen blockade.

Anticancer research

Previous studies have reported that tumor cells' adhesion to quiescent endothelial cell is me... more Previous studies have reported that tumor cells' adhesion to quiescent endothelial cell is mediated by beta-1 integrins. The aim of this study was to determine the role beta-1 integrins play in prostate cancer cell adhesion to human bone marrow endothelial cells (HBME) and human aortic endothelial cells (HAEC). A well described blocking antibody to beta-1 integrin subunit was used in adhesion assays to determine the role of beta-1 integrin subunit in the adhesion of PC-3 cells to both HBME cells and HAEC. Antibody to the beta-1 integrin subunit failed to reduce PC-3 adhesion to HBME and HAEC, yet this same antibody significantly reduced adhesion of PC-3 cells to fibronectin coated wells. The data suggest that metastasis of prostate cancer cells to bone may be mediated, in part, by preferential adhesion to HBME cells; but beta-1 integrins most likely are not involved in this interaction.

International journal of oncology, 2000

Recent studies have provided convincing evidence for the role of soy-isoflavones, particularly ge... more Recent studies have provided convincing evidence for the role of soy-isoflavones, particularly genistein, in the inhibition of prostate cancer cell growth. Prostate specific antigen (PSA) is a biological marker used to detect and monitor the treatment of prostate cancer patients. Previous studies have documented that isoflavones can inhibit the secretion of PSA in the androgen-dependent prostate cancer cell line, LNCaP, however, the effects of genistein on androgen-independent PSA expression has not been explored. In this study, we have utilized a prostate cancer cell line, VeCaP, which expresses PSA in an androgen-independent manner, to determine the effects of genistein on cell proliferation and PSA expression. Here we show that genistein inhibits cell growth similarly in both the LNCaP and VeCaP cell lines, but has differential effects on PSA expression. We demonstrate using concentrations of genistein that have been detected in the serum of humans consuming a soy-rich diet, that...

Anticancer research

Gemcitabine has demonstrated clinical activity against several common cancers. Our studies examin... more Gemcitabine has demonstrated clinical activity against several common cancers. Our studies examine the ability of gemcitabine, both alone and in combination with other chemotherapeutic agents, to inhibit the in vitro and in vivo growth of several prostate cancer cell lines. Cultures of LNCaP, PC-3 or MLL cells were exposed to either gemcitabine or other appropriate agents for specified amounts of time. Cells were lysed and nuclei counted utilizing a Coulter Counter. For in vivo experiments, animals were injected with 1 x 10(5) MLL cells subcutaneously into the right flank. Animals were treated as indicated for 14 days. Tumors were then excised, weighed and measured. In both human (PC-3 and LNCaP) and rat prostate (MLL) cancer cell lines our studies demonstrated gemcitabine had a strong effect in vitro, with an IC50 of approximately 500 nM in the human lines and 10 nM in MLL cells. In vivo, studies using the Dunning prostate cancer model in Copenhagen rats resulted in a dose response...

Clinical cancer research : an official journal of the American Association for Cancer Research, 2000

In this report, we describe the distribution of metastases from 14 patients who had hormone-refra... more In this report, we describe the distribution of metastases from 14 patients who had hormone-refractory adenocarcinoma of the prostate and agreed while alive to undergo directed autopsies after their deaths. These autopsies were undertaken specifically to document the distribution of metastases, characterize tumors phenotypically and immunohistochemically, harvest fresh and snap frozen tumor and normal control tissues suitable for molecular examination, and establish cell lines via passages through generations of severe combined immunodeficient and athymic mice. Achievement of these goals was obtained through the development of a multidisciplinary team approach. Team members included a medical oncologist, pathologists, urologists, and researchers. The autopsy and tissue procurement teams were available on a round-the-clock basis. The tissues harvested from these autopsies yielded high-quality tumor samples, as evidenced by excellent preservation seen by light microscopy, strong prost...

Cancer research, Jan 15, 2000

Using naturally serum-free SU-ECM basement membranes as invasion substrates showed that plasma fi... more Using naturally serum-free SU-ECM basement membranes as invasion substrates showed that plasma fibronectin was necessary to stimulate invasion by DU 145 human and metastatic MATLyLu (MLL) rat prostate carcinoma cells. This activity mapped to the PHSRN sequence, which induced invasion through alpha5beta1 integrin. PHSCN, a competitive inhibitor, blocked both PHSRN- and serum-induced invasion. Acetylated, amidated PHSCN (Ac-PHSCN-NH2) was 30-fold more potent; however, Ac-HSPNC-NH2 was inactive. Rats receiving injections s.c. with 100,000 MLL cells were treated systemically by i.v. injection three times weekly with 1 mg of either Ac-PHSCN-NH2 or Ac-HSPNC-NH2 beginning 24 h later, three times weekly with 1 mg of Ac-PHSCN-NH2 beginning only after surgery to remove large (2 cm) MLL tumors, or were left untreated. MLL tumors grew rapidly in Ac-HSPNC-NH2-treated and in untreated rats. MLL tumor growth in rats treated with Ac-PHSCN-NH2 beginning 1 day after MLL cell injection was reduced by ...

Clinical cancer research : an official journal of the American Association for Cancer Research, 2000

Preclinical and in vitro studies have determined that copper is an important cofactor for angioge... more Preclinical and in vitro studies have determined that copper is an important cofactor for angiogenesis. Tetrathiomolybdate (TM) was developed as an effective anticopper therapy for the initial treatment of Wilson's disease, an autosomal recessive disorder that leads to abnormal copper accumulation. Given the potency and uniqueness of the anticopper action of TM and its lack of toxicity, we hypothesized that TM would be a suitable agent to achieve and maintain mild copper deficiency to impair neovascularization in metastatic solid tumors. Following preclinical work that showed efficacy for this anticopper approach in mouse tumor models, we carried out a Phase I clinical trial in 18 patients with metastatic cancer who were enrolled at three dose levels of oral TM (90, 105, and 120 mg/day) administered in six divided doses with and in-between meals. Serum ceruloplasmin (Cp) was used as a surrogate marker for total body copper. Because anemia is the first clinical sign of copper def...

Anticancer research

Most deaths from prostate cancer result from the metastatic spread of the disease. Castanospermin... more Most deaths from prostate cancer result from the metastatic spread of the disease. Castanospermine has been shown to inhibit tumor growth and metastasis in mouse and rat models. We hypothesized that castanospermine might inhibit metastasis in the Dunning model of rat prostate adenocarcinoma by interfering with the metastatic properties of tumor cells. We examined the cytotoxicity of castanospermine toward the metastatic MAT-LyLu and nonmetastatic AT. 1 cell lines and its effects on cell motility and adhesion to endothelial cells. We assessed castanospermine's effects on in vivo metastasis in Copenhagen rats. Castanospermine was not cytotoxic toward the MAT-LyLu and AT. 1 cell lines at concentrations through 10 micrograms/mL, nor did it significantly affect cell motility, adhesion to endothelial cells, or in vivo metastasis. Within the Dunning model, castanospermine did not appear to significantly affect cell characteristics related to metastatic potential.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 1994

Estramustine and etoposide (VP-16) have been demonstrated to inhibit the growth of prostate cance... more Estramustine and etoposide (VP-16) have been demonstrated to inhibit the growth of prostate cancer cells in experimental models. This led us to evaluate the effectiveness of this combination in the treatment of patients with metastatic prostate carcinoma refractory to hormone therapy. Estramustine 15 mg/kg/d and VP-16 50 mg/m2/d, were administered orally in divided doses for 21 days. Patients were then taken off therapy for 7 days and the cycle then repeated. Therapy continued until evidence of disease progression. Forty-two patients have been enrolled onto this trial with a minimum of 40 weeks follow-up. Of 18 patients with measurable soft tissue disease, three demonstrated a complete response (CR) and six a partial response (PR) for longer than 2 months. Of these 18 patients, pretreatment prostate-specific antigen (PSA) levels decreased by at least 75% in five men (28%) and by at least 50% in nine (50%). The median survival duration has not been reached in those patients who demon...

Anticancer research

All solid tumors require the induction of new blood vessels to grow. To begin to study this pheno... more All solid tumors require the induction of new blood vessels to grow. To begin to study this phenomenon in prostate cancer, we investigated the intensity of tumor associated angiogenesis in prostate non malignant and malignant tissue. Angiogenesis was measured by quantitating microvessels in a total of 67 patients: 23 non malignant biopsy specimens, and 34 malignant specimens from patients who had undergone prostatectomy. Angiogenic activity in prostatic cancer (prostatectomy) tissue (utilizing Factor VIII staining) was then correlated with pathological staging (Whitmore-Jewitt). Overall there appeared to be a trend of increasing microvessel count (MVC) from benign through the advancing stages of prostate cancer. Based on mean microvessel counts we were able to distinguish stage D from all other pathological stages (p = 0.004 between stages C and D). There was, however, no statistically significant difference between stage B and C. We conclude that tumor associated angiogenesis in pr...

Anticancer research

Maltose tetrapalmitate (MTP), a non-toxic synthetic glycolipid analog of lipid A, has been shown ... more Maltose tetrapalmitate (MTP), a non-toxic synthetic glycolipid analog of lipid A, has been shown to have antitumor activity in tumor-transplanted animals. Its mode of action has been postulated to be as an immunoadjuvant or as an anti-angiogenesis agent. MTP has been shown to have antitumor properties in lung, bladder, mammary, colon, liver and soft tissue tumors, but its action on prostate cancer has not yet been investigated. The effect of MTP alone and in combination with hydrocortisone hemisuccinate on prostate cancer and the ability of MTP to inhibit angiogenesis were examined in this study. In vitro, MTP was minimally cytotoxic to rat prostate cancer cells and to bovine and human endothelial cells at high concentrations. In the angiogenesis inhibition assays, the MTP alone exhibited no anti-angiogenesis effect and significant anti-angiogenesis activity only when combined with hydrocortisone hemisuccinate at high doses. In vivo, however, MTP demonstrated significant inhibition ...

International Journal of Oncology, 1995

Hormone refractory prostate cancer remains an incurable disease and the discovery of newer agents... more Hormone refractory prostate cancer remains an incurable disease and the discovery of newer agents with higher cytotoxic activity is required. Gossypol is a phenolic compound isolated from cottonseed oil which has been shown to have anti-spermatogenic effects. In in vitro studies, gossypol appears to inhibit the growth of rat prostate cancer cell line MAT-LyLu and human prostate adenocarcinoma cell lines PC-3, LNCaP and DU-145. In vive, gossypol appeared to inhibit tumor growth of subcutaneously implanted MAT-LyLu cells in Copenhagen rats. Gossypol may be an active agent for the treatment of hormone refractory metastatic prostate cancer.

Cancer research, Jan 15, 1989

The present study investigated the in vitro and in vivo antitumor effects of gossypol on human SW... more The present study investigated the in vitro and in vivo antitumor effects of gossypol on human SW-13 adrenocortical carcinoma cells. In vitro gossypol concentrations greater than or equal to 0.5 microM reduced the growth rate of the SW-13 cells. Membrane microviscosity was determined by fluorescence polarization of diphenylhexatriene. The membranes of viable SW-13 cells exposed to gossypol became more rigid after a 1-day exposure to gossypol, the polarization constant, P, increasing from 0.229 to 0.352. Gossypol also increased the microviscosities of isolated mitochondrial and microsomal enriched membrane preparations. Tumor was also transplanted into nude mice by s.c. injection of SW-13 cells. A 1-week pretreatment period followed by daily administration of gossypol in which 30 mg gossypol/kg body weight/day was administered via orogastric tube delayed the onset of visible tumor in the subsequent weeks. Five weeks after transplantation, tumor prevalence rate was 95.8% in the contro...

Critical reviews in eukaryotic gene expression, 1991