Biomedical subjects

M Rubenstein

Publications and source records attributed to M Rubenstein.

At least 19 recordsLinked to original sources

PubMed2006

To what extent are the "sets" of biologic properties expressed by hypoxic cancer cells and by cancer "stem" cells equivalent, intersecting, disjoint or complementary? Some implications for the design of cancer therapies.

Resistance to various cancer therapies with survival or recurrence of a malignancy has been ascribed to the inability to "kill" hypoxic cancer cells. The reported resistance of cancer "stem" cells has also been proposed as a major reason for this outcome. In planning therapy, it should be important to know whether these two categories "overlap": do "hypoxic" cells subsume cancer "stem" cells; alternately, are "stem" cells somewhat hypoxic or are these categories distinct? If the former is true and these categories overlap, to what extent do their properties share biochemical elements in common; if the latter is the case, should both properties be "targeted" independently? The inability of a proposed therapy to suppress these foci of resistance could preclude a successful outcome. Results from pre-clinical and clinical laboratory determination of the stem cell/hypoxic cell response may reflect the likely outcome of the proposed clinical treatment.

Animals↗

PubMed2006

Bispecific antisense oligonucleotides with multiple binding sites for the treatment of prostate tumors and their applicability to combination therapy.

Antisense oligonucleotides (oligos) against transforming growth factor-alpha (TGF-alpha; MR(1)) and its binding site, the epidermal growth factor receptor (EGFR; MR(2)), have proven efficacious against PC-3 and LNCaP prostate tumors when evaluated in both in vitro and in vivo models. To enhance their activity, and also to introduce a significantly different type of multifunctional agent into this field, "bispecific" oligos were constructed containing truncated sequences (derived from MR(1) and MR(2)) recognizing both TGF-alpha and EGFR mRNA internal binding sites, located about their respective AUG initiation codons. Two bispecifics were constructed, each having complementary sequences for TGF-alpha and EGFR mRNA, but differing in their 5' to 3' tandem orientation (TGF-alpha/EGFR [MR(12)] and EGFR/TGF-alpha [MR(21)] sequences). These bispecifics were tested in an in vitro system against PC-3 and LNCaP prostate tumor cells, with comparisons made to the original monospecific oligos from which they were derived. Efficacy was also compared when administered either alone or in combination with conventional chemotherapeutic agents. The purpose of this study was: 1) to validate the concept that these newly developed bispecific oligos have antitumor activity; 2) to enhance their efficacy through combination therapy; 3) to identify differences in effectiveness dependent upon binding site orientation; 4) identification of a dominant binding site that can be used to design other bispecifics that target additional tumor regulatory pathways. When fully evaluated against PC-3 cells in a series of experiments, newly developed bispecific oligos are at least as effective as their monospecific counterparts from which they were derived, and the bispecific with the MR(21) orientation is notably more effective than the MR(1) monospecific by 64% (p = 0.014 by Student t-test and p = 0.068 by the more stringent Mann-Whitney U test). Bispecifics were more effective when administered with chemotherapeutics (producing inhibition of 52.1% and 61.2% for MR(12) and MR(21), respectively, with Cytoxan (cyclophosphamide) inhibition of 59.0% and 65.1% for MR(12) and MR(21), respectively, with Taxol (paclitaxel) and 63.0% and 69.4% for MR(12) and MR(21), respectively, with DES [diethylstilbestrol]). Increasing the oligo concentration above 6.25 microM with cyclophosphamide had no additional effect. The sequence directed against EGFR was dominant and contributed most to bispecific activity, particularly when inserted 5' to the TGF-alpha binding sequence (MR(21) orientation). Bispecific oligos are a significant advance in the design of antisense compounds and could play a role in treating prostate cancer, particularly when they are administered with traditional chemotherapeutics. The truncated portion of the MR(2) oligo used here should be included when constructing second-generation bispecifics that target proteins associated with other regulatory pathways, such as apoptosis.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Disparate forms of MK 886-induced programmed death in BCL-2 (+) blood and BCL-2 (-) solid cancer cells and a putative "nuclear" Ca2+ channel: "soil" trumps "seed"?

UNLABELLED: The five-lipoxygenase inhibitor, MK 886, in micromolar concentration induces a "type 1" form of programmed cell death in U937 human monoblastoid cells and a "type 2" form in Panc-1 pancreatic and PC3 prostate cell lines. The latter two lines originate from epithelial-derived solid human cancers. An acute rise in Ca(2+) occurs in U937 and HL 60 myeloid cells, in U937 cells located in their nuclei (HL 60 not tested), both of which are Bcl-2 positive. The two solid cancer cell lines express neither of these features. Solid tumor-derived Bcl-2-positive HeLa cervical cancer cells exhibit an acute increase in Ca(2+) after challenge with MK 886. In U937, PC3 and Panc-1 cells tested, the agent acutely increases oxidative stress and decreases mitochondrial membrane potential, indicating that neither event is directly determinative for the form of PCD. The role of mitochondria and the mechanism by which increased oxidative stress initiates the acute rise in U937 "nuclear" Ca(2+), the contribution, if any, of Bcl-2 in initiating the Ca(2+) signal and the latter in mandating the type of PCD, presumably through differential modulation of transcription, remain to be determined. Lastly, these results demonstrate that "soil" trumps "seed". HYPOTHESIS: Despite similarities in response, including those of the mitochondria to micromolar concentrations of MK 886, hematopoietic and epithelial-derived non-hematopoietic solid cancer cell lines exhibit dissimilar forms of programmed cell death. These differences may depend upon the presence of Bcl-2 or a related protein participating in a juxta-nuclear/nuclear Ca(2+) ion-channel. Evidence for this supposition is discussed.

Apoptosis↗

PubMed2002

Backbone modification alters the efficacy of antisense oligonucleotides directed against mRNA encoding either TGF-alpha or EGFR in the treatment of prostate cancer cell lines.

Antisense oligonucleotides (oligos) directed against mRNA-encoding, transforming growth factor-alpha (TGF-alpha) and the epidermal growth factor receptor (EGFR), have been shown to significantly inhibit in vitro and in vivo growth of prostate tumor models. Recently, second generation oligos have been employed with identical base sequences, but containing backbome modifications that enhance stability, solubility and circulatory patterns. Using relatively low concentrations of oligos, we compared the efficacy of the first generation phosphorothioated oligos against TGF-alpha (MR1) and EGFR (MR2) with second generation oligos containing completely phosphorothioated backbones and different patterns of 2'-methoxyethyl (2'-MOE) backbone modifications, while retaining the original designated base sequence using, the LNCaP and PC-3 prostate cancer cell lines, respectively. All experiments were conducted in vitro with lipofectin to enhance oligo entry. Under these conditions, using oligo concentrations between 0.83 and 3.32 microM for LNCaP cells treated with oligos directed against TGF-alpha only the first generation MR1 had inhibitory activity. When treated with oligos directed against EGFR, none of the oligos had inhibitory activity and they behaved similarly. Using the PC-3 cell line and treatment directed against TGF-alpha with oligo concentrations between 0.42 and 3.32 microM, first generation MR1 and second generation 5005 behaved similarly with no notable effect, while second generation 5007 produced dramatic growth stimulation. When PC-3 cells were treated with oligos directed against EGFR, second generation 5006 and 5008 had similar and apparently dose-dependent inhibition. We conclude that backbone modifications influence oligo efficacy and may result in either enhanced or diminished activity. Because of their activity against the hormone insensitive PC-3 cells, the 5006 and 5008 compounds warrant additional study at greater concentrations and also merit in vivo testing.

ErbB Receptors↗

PubMed2001

Biotinylation of antisense oligonucleotides does not alter lipofectin enhanced cellular uptake in prostate cancer cell lines.

Biotinylation is a common modification made to pharmaceuticals, including antisense oligonucleotides (oligos), to enhance their specific delivery. Such agents bind to targets that have been previously labeled with conjugated avidin, or alternatively, heteroconjugate monoclonal antibodies that have dual biotin and tumor-specific antigen specificities may be employed. However, for a drug to be efficacious it must also be taken up by the targeted cells. This is frequently difficult for large molecular weight compounds and cationic lipids, like lipofectin, are often employed. However, the effect of biotinylation on oligo uptake has not been examined in the presence of lipofectin, particularly in prostate cancer cells. Oligos conjugated with biotin and FITC were incubated in vitro with LNCaP and PC-3 cells in the presence of a previously determined effective concentration of lipofectin. Fluorescent uptake and distribution was compared to similar oligos that were not biotinylated. The results demonstrate that biotinylation does not alter the uptake of oligos in LNCaP or PC-3 prostate cancer cells, nor does it alter their retention or cytoplasmic distribution in PC-3 cells when used with lipofectin.

Biotinylation↗

PubMed2001

Treatment of the T98G glioblastoma cell line with antisense oligonucleotides directed toward mRNA encoding transforming growth factor-alpha and the epidermal growth factor receptor.

Antisense oligonucleotides (oligos) complementary to mRNA encoding transforming growth factor-alpha (TGF-alpha) and its target, the epidermal growth factor receptor (EGFR), are efficacious against human prostate and breast cancers carried in athymic nude mice. Glioblastomas, also regulated by EGFR expression, would appear to be similarly susceptible, and we now employ them against the T98G tumor model. T98G cells were distributed into wells and allowed to adhere prior to addition of oligos (12.5 microM) directed against TGF-alpha and/or EGFR for 6 d of treatment before thymidine radiolabeling. Supplemental media and oligos (25 microM final concentration) were added after d 3. Statistically significant inhibition by oligos directed against TGF-alpha, EGFR, and their combination was 13.8%, 26.3%, and 18.1%, respectively. In a subsequent experiment cells were incubated with increasing amounts of each oligo and their combination for 3 d prior to radiolabeling. Statistically significant inhibition of growth for either oligo at every concentration was found. Cells incubated with 6.25, 12.5, 25, and 50 microM antisense directed against TGF-alpha had a mean inhibition of 29.3%, 33.3%, 21.7%, and 46.6%, respectively. Cells similarly treated with oligos against EGFR had a mean inhibition of 77.9%, 80.3%, 82.0%, and 83.7%, respectively, and cells incubated with 6.25, 12.5, 25 and 50 microM of each oligo had a mean inhibition of 74.7%, 70.6%, 70.8%, and 76.3%, respectively. Lastly, in a paired experiment, cells treated with 0, 0.39, 0.78, 1.56, 3.125, and 6.25 microM of oligos, either specifically directed against EGFR or a random control, for 3 d were evaluated for both thymidine incorporation and EGFR expression. Statistically significant inhibition of 3H-thymidine incorporation was seen in cells with the oligo specifically directed against EGFR at 3.125 microM and 6.25 microM when compared to non-oligo containing controls. This was accompanied by a comparable significantly decreased expression of a low-MW reactive derivative of EGFR at 3.125 microM and 6.25 microM in Western blots, and of a high-MW reactive EGFR at 6.25 microM. The significant effect against high-MW EGFR was observed vs both the non-oligo containing control and the random sequence. Oligo concentrations between 0.78 and 1.5 microM also resulted in decreased expression of the low-MW form, but not significant differences in thymidine radiolabeling. In recovery experiments, cells treated initially with greater oligo concentrations required significantly increased time to recover, particularly in cells treated with EGFR directed oligos. Intracellular uptake and nuclear localization was demonstrated with FITC tagged oligos. In summary, even at relatively low oligo concentrations and short exposure, oligos against TGF-alpha, and particularly EGFR, significantly inhibit in vitro growth of the T98G glioblastoma, possibly mediated by decreased EGFR expression.

Blotting, Western↗

PubMed2000

Changes in radical prostatectomy and radiation therapy rates for African Americans and whites.

There are racial differences in prostate cancer outcomes. One variable influencing end results is treatment for cure: either radical prostatectomy (RP) or radiation therapy (RT). The purpose of this report is to determine changes in diagnosis rates of localized prostate cancer between the years before prostate-specific antigen (PSA) use (1973-1988) and the years after PSA use (1989-1996), to evaluate differences in RP and RT rates between the pre-PSA and post-PSA eras, to assess differences in RP and RT rates between African Americans and whites between these intervals. The Surveillance, Epidemiology, and End Results (SEER) data were used and evaluated. Both African Americans and whites had statistically increased rates of localized prostate cancer diagnosed (70.4 and 49.0 in 1973 through 1988 and 123.1 and 84.9 in 1989 through 1996, respectively [p < 0.05]). The differences between the pre-PSA and post-PSA eras for African Americans and whites for RP (3.6 vs. 44.3 and 5.0 vs. 44.9, respectively) and RT (23.6 vs. 61.6 and 17.0 vs. 38.1, respectively) were all significant (p < 0.05). Both African Americans and whites had increased rates of RP from 3.6 and 5.0 to 44.3 and 44.9, respectively, and RT from 23.6 and 17.0 to 61.6 and 38.1 during the pre- and post-PSA years.

Black or African American↗

PubMed1998

An evaluation of the markers p53 and Ki-67 for their predictive value in prostate cancer.

BACKGROUND AND OBJECTIVES: p53 and Ki-67 are but two markers being evaluated for their predictive value in prostate cancer. The purpose of this study was to compare p53 and Ki-67 with age, stage, Gleason score, and ploidy for their prognostic abilities in prostate cancer. METHODS: Prostate cancer specimens from 134 patients were immunohistochemically stained for p53 and Ki-67 expression and differences evaluated by SPSS analysis of variance (ANOVA) methods. The dependent variable was patient survival and the independent variables were age, stage, Gleason score, and ploidy. RESULTS: In decreasing order of prediction of survival were stage (P < 0.001), Gleason score (P < 0.001), age (P = 0.1869), Ki-67 (P = 0.2284), p53 (P = 0.4282) and ploidy (P = 0.8141). CONCLUSION: It is concluded that stage and Gleason score are significant predictors of survival while p53, Ki-67, age and ploidy are not.

Aged↗

PubMed1998

Growth factor deprivation therapy of hormone insensitive prostate and breast cancers utilizing antisense oligonucleotides.

Antisense oligonucleotides (oligos) are artificial sequences of nucleotide bases which may be synthesized complementary to known regions within specific mRNAs. When these constructed oligos interact with protein encoding mRNA they may regulate expression of various growth factors and/or their receptors. Oligos directed against transforming growth factor-alpha (TGF-alpha) and its binding site, the epidermal growth factor receptor (EGFR), were employed: A) in vitro to affect the growth of hormone insensitive human derived PC-3 prostate cancer cells as well as the human derived UACC-893 breast cancer cell line; and B) in vivo to treat tumors established by these cell lines in athymic nude mice. The in vitro results for each oligo, and their combination, produced significant inhibition of both prostate and breast cell lines. In addition, the combination of oligos most efficiently diminished the immunohistochemical expression of both TGF-alpha and EGFR in PC-3 cells. Direct in vivo inoculation of oligos into established PC-3 or UACC-893 tumors in nude mice produced hemorrhagic necrosis within 2-3 days. Such therapy could represent a new tier of therapy for recurrent, hormone insensitive, tumors based upon the concept of growth factor deprivation.

Animals↗

PubMed1998

Paclitaxel, bropirimine and linomide: effect on growth inhibition in a murine prostate cancer model by different growth regulatory mechanisms.

Paclitaxel, bropirimine and linomide therapy was evaluated in a murine prostate cancer model. All drugs were effective in impeding tumor growth but the mechanisms of action varied. Paclitaxel inhibited bcl-2 expression suggesting an apoptotic mechanism. Bropirimine, while inhibiting bcl-2 expression also significantly depressed tumor necrosis factor-alpha (TNF-alpha) expression. In the bropirimine treated group there was also a correlation between angiogenesis and cyclin D expression. Finally, linomide significantly decreased angiogenesis. Since the mechanism of action of these drugs differ, combining them at lower doses might maintain therapeutic efficacy while reducing toxicity.

Animals↗

PubMed1998

Paclitaxel is more effective than thalidomide in inhibiting LNCaP tumor growth in a prostate cancer model.

LNCaP tumors were treated by either administration of paclitaxel, thalidomide or by orchiectomy in order to determine their relationship with markers pertaining to the process of tumor growth, apoptosis or angiogenesis. Forty rats bearing LNCaP tumors were divided into 4 groups of 10 and treated by either paclitaxel (20 mg/kg x 5 days); thalidomide (200 mg/kg x 5 days/week x 5 weeks); or orchiectomy. After 6 weeks serum samples were removed for PSA determination and the animals sacrificed for evaluation of: A) tumor volume; B) tissue bcl-2, cyclin D, PSA and factor VIII immunohistochemically graded (0-5 scale) for marker expression; and C) serum PSA. Comparisons were made to untreated LNCaP tumors. Statistically significant differences were determined using the nonparametric Mann-Whitney test. Paclitaxel produced significant differences in volume (p < 0.001), expression of bcl-2 (p < 0.043), cyclin D (p < 0.023), tissue PSA (p < 0.001) and serum PSA (p < 0.019) levels. Thalidomide altered expression of bcl-2 (p < 0.011) and tissue PSA (p < 0.002). Orchiectomy altered volume (p < 0.002) and bcl-2 expression (p < 0.001). All three therapies have been suggested for prostate cancer and each produced alterations in accepted markers for treatment response (either reduced volume or serum PSA). Paclitaxel significantly influenced the most markers. Of interest was that all treatments, especially thalidomide, a known antiangiogenesis agent, reduced factor VIII, although not significantly. Evidently each treatment evokes different pathways of activity.

Androgen Antagonists↗

PubMed1997

Report of 337 patients with renal cell carcinoma emphasizing 110 with stage IV disease and review of the literature.

BACKGROUND: In the literature, the interdependence of variables, including stage, sex, age, tumor size, therapy, and survival, is complex. The size variable has heretofore received relatively little emphasis. METHOD: This was a retrospective evaluation of 337 patients with kidney cancer treated at the University of Illinois Affiliated Hospitals. Data were collected on stage, sex, age, tumor size, TNM stage, therapy, and survival. Statistical analyses included Kaplan-Meier 5-year survivals, as well as multivariate analysis utilizing the Cox regression model. A subset of 110 patients with TNM Stage IV disease is further evaluated employing a multivariate analysis. The principal form of therapy was nephrectomy. RESULT: Five-year survivals by stage varied from 100% for Stage I, 96% for Stage II, 59% for Stage III, to 16% for Stage IV. In the subset of 110 patients with TNM Stage IV disease, those with a single metastasis had better survivals than those with two or more. Those having nephrectomy had better survivals (P < 0.05). Therapy (in addition to nephrectomy) was curative (defined as cytotoxic chemotherapy or immunotherapy) in 40 patients and palliative (defined as radiation to bone metastases, hormone therapy, or supportive) in 70 patients. Multivariate analysis of TNM Stage IV variable differences indicated that only tumor size differences and nephrectomy significantly affected survival. CONCLUSIONS: Of importance is the observation that among these patients. Survival is directly correlated with tumor size.

Adenocarcinoma↗

PubMed1997

Enhanced expression of bcl-2 following antisense oligonucleotide mediated growth factor deprivation.

Although the role of bcl-2 in apoptosis has been described, its involvement in prostate cancer (CAP) progression is less well understood, but thought to be involved with the transition of CAP from androgen-sensitivity to androgen-independence, where its expression is augmented following androgen ablation. For treating these recurrent androgen-independent tumors, following hormone treatment failure, a new tier of therapy based upon growth factor deprivation has been suggested, implemented by antisense oligonucleotides (oligos) directed against mRNA encoding a critical growth regulatory autocrine loop (comprised of transforming growth factor-alpha (TGF-alpha) and its binding site, the epidermal growth factor receptor (EGFR). To determine whether oligo-induced growth factor deprivation therapy similarly enhanced expression of bcl-2 (as follows androgen deprivation) human prostate cancer derived PC-3 cells were treated in vitro with oligos directed against TGF-alpha (MR-1) and/or EGFR (MR-2). After 5 days of treatment cells were immunochemically stained for human bcl-2. In similar experiments, cells were treated for 3 days prior to extraction of proteins, Western blot analysis, photography and computer evaluation of protein density by SigmaScan software. Immunostained cells treated with oligos directed against mRNA encoding TGF-alpha (MR-1) either alone or in combination with that directed against EGFR (MR-2) had increased bcl-2 expression (+3 to +5). In addition, the intensity of Western blots scanned for bcl-2 expression were 19%, 32% and 30% greater in cells treated with oligos directed against TGF-alpha, EGFR or their combination, respectively. We conclude that enhanced bcl-2 expression followed antisense oligo induced growth factor deprivation. This result is similar to that found upon androgen deprivation therapy, and also demonstrates additional biologic activity of this new class of molecular therapeutic agents.

Apoptosis↗

PubMed1997

Bropirimine as neoadjuvant therapy decreases residual disease and expression of markers PCNA and TGF-beta 1 in a rat orthotopic prostate adenocarcinoma.

The role of bropirimine in prostate cancer remains unexplored. To address the efficacy of this immune modulator as neoadjuvant therapy we utilized the orthotopic placement of the Dunning AT-3 tumor. 2.4-2.6 x 10(6) Dunning AT-3 cells were injected into the ventral prostates of 50 Copenhagen X Fischer rats. Animals were then divided into 5 groups consisting of: 1) untreated controls; 2) those treated with ventral prostatectomy alone (performed 10-12 days following tumor cell inoculation); 3) those treated with ventral prostatectomy plus bropirimine (10 mg/kg) on postimplantation days 1, 3, 5, 10 and 11; 4) those treated with ventral prostatectomy plus bropirimine (100 mg/kg), at the same schedule; and 5) those treated with ventral prostatectomy plus bropirimine (500 mg/kg), at the same schedule. Animals were sacrificed 10 days after prostatectomy, autopsied, and residual disease was weighed. Prostate weights upon removal following neoadjuvant treatment and residual disease remaining after 20-22 days were expressed in grams (g). Following prostatectomy, mean prostate weights were: Group 2, 0.67 +/- 0.11; Group 3, 0.53 +/- 0.11; Group 4, 0.54 +/- 0.12; Group 5, 0.44 +/- 0.09. The effect of bropirimine was significant (p = 0.0001) by multiple regression analysis. In addition, mean residual tumor weights (expressed in grams) after 20-22 days were: Group 1, 12.7 +/- 1.9; Group 2, 6.7 +/- 4.8; Group 3, 5.2 +/- 5.9; Group 4, 3.8 +/- 3.5; and Group 5, 2.8 +/- 3.5. The effect of bropirimine was not significant (p = 0.07) by multiple regression analysis. However, prostatectomy alone, by Student's test, significantly (p = 0.04) reduced residual mean tumor weights by 47% and the additional effect of bropirimine upon residual disease was significant (p = 0.038) if a Chi-square analysis is applied. Finally, a multivariate analysis of the overall effect of bropirimine in rats treated with prostatectomy was significant (p = 0.002). The effect of bropirimine on expression of proliferating cell nuclear antigen (PCNA) and transforming growth factor beta 1 (TGF-beta 1) was also evaluated immunohistochemically and expression of both tumor markers was significantly reduced (p < 0.05). We conclude that bropirimine may have a role as a neoadjuvant therapy when combined with prostatectomy.

Adenocarcinoma↗

PubMed1996

Antisense oligonucleotide intralesional therapy for human PC-3 prostate tumors carried in athymic nude mice.

Previously we reported hemorrhagic necrosis in human-derived PC-3 prostate tumors, in athymic nude mice, produced by the intralesional injection of antisense oligonucleotides (oligos) directed against mRNAs encoding transforming growth factor-alpha (TGF-alpha) and its target, the epidermal growth factor receptor (EGFR). We now describe our experience with these oligos in treating additional mice with various doses and modes of administration. During prolonged treatment, a dose-response effect was observed, with the optimal dosage consisting of the combination of 400 micrograms of each oligo. Although responses varied, based upon amount and how oligos were administered, we found that tumors were best treated when initially less than 156 mm3. Intralesional inoculations produced necrosis and yielded responses, ranging from complete response (CR) or cure to partial responses (PR) in 9 of 12 tumors treated with full dose (400 micrograms of each oligo) and 1 of 1 treated with 800 micrograms of each oligo, against a large tumor. Included among the 9 positive responses with full-dose administration were 2 tumors that regressed (one completely). A single tumor treated with twice (2X) the normal dosage (800 micrograms of each oligo) also regressed. A single tumor treated with half (1/2) dose (200 micrograms of each) progressed similar to controls, as did 3 of 12 treated with the full dose. Limited experience with ALZET diffusion pumps gave CR (1 of 3) or PR (2 of 3) in 100% of tumors treated (including one mouse cured of multiple tumors in a five day period). It appears that multiple inoculations consisting of 400 micrograms of each oligo is most effective against these tumors, particularly when administered against tumors of <156 mm3 in initial size.

Animals↗

PubMed1996

Suramin as adjuvant therapy with radical prostatectomy.

Suramin is a newer agent employed in the management of prostate cancer. One suggested method of action is growth factor inhibition. While suramin has been employed to treat advanced disease its adjuvant role remains unexplored. To address this question we have employed a new model: the orthotopic placement of the Dunning AT-3 tumor. The purpose of this research was to assess the efficacy of adjuvant therapy in controlling residual disease. The method consisted of the injection of 2.4 to 2.6 x 10(6) AT-3 cells (harvested from flank tumors) into the ventral prostates of 29 Copenhagen X Fischer rats. The animals were then divided into four groups: 1) untreated controls (6 rats); 2) ventral prostatectomy only (10 rats); 3) ventral prostatectomy plus suramin (300mg/Kg) on post-op day 3 (5 rats); and 4) ventral prostatectomy plus cytoxan (50 mg/Kg) on post-op day 3 (8 rats). Prostatectomies were performed 10-12 days following AT-3 cell inoculation. Animals were sacrificed 10 days following prostatectomy, autopsied, and residual diseased weighed. All operating procedures: tumor cell inoculations, ventral prostatectomies, and necropsies were performed microsurgically employing a Zeiss operating microscope. The results (in mean tumor weights) were: Group 1, 20 +/- 1.4 gms; Group 2, 6.7 +/- 11.5 gms; Group 3, 2.7 +/- 3.8 gms; and Group 4, 2.2 +/- 2.5 gms. The differences between control and all treatment groups were significant: Group 1 vs. Group 2, P < 0.02; and Group 1 vs. Groups 3 and 4, P < 0.001. We conclude that prostatectomy resulted in a diminished weight of residual disease. Of more importance was the fact that adjuvant therapy further reduced residual disease. The orthotopic placement of the Dunning tumor may serve as a model to evaluate the place of suramin following radical prostatectomy.

Animals↗

PubMed1996

Antitumor effect of CPT-11, a new derivative of camptothecin, against human prostate cancer (PC-3) in vitro and prostate rat tumor (AT-3) in vivo.

In an effort to evaluate the efficacy of CPT-11 on prostate cancer we utilized the PC-3 human prostate cancer cell line (in vitro), and the Dunning R3327 AT-3 rat prostate cancer tumor line (in vivo). PC-3 cells were initially seeded and cultured prior to the addition of CPT-11 at different concentrations 48 and 120 h later. After an additional 48 h the number of cells was determined using MTT dye uptake. CPT-11 at concentrations between 10 ng/ml and 50 micrograms/ml inhibited the growth of the PC-3 prostate human cancer cell line up < 0.001). AT-3 prostate rat cancer cells were injected into the right flank of 30 Copenhagen X Fischer rats, divided into treated and control groups. A total dose of CPT-11 (200 mg/kg) was given intraperitoneally, administered 1, 3 and 5 days postimplantation. We evaluated tumor growth by size and weight (5 and 10 days postimplantation). A total dose of 200 mg/kg inhibited the rapid growth of the prostate AT-3 tumor in vivo (p < 0.001).

Animals↗

PubMed1995

Renal cell carcinoma: comparison of the TNM and Robson stage groupings.

This review compares the two major staging systems for renal cell carcinoma: the TNM and Robson systems. For purposes of worldwide clinical and scientific consistency, the TNM system is recommended. However, the primary tumor size cutoff of 2.5 cm. does not prognostically differentiate between stages I and II. A review of 337 patients with renal cell carcinoma, of whom 122 had stage I or II disease revealed that a 2.5-cm cutoff did not predict survival differences, while cutoffs of 5.0, 7.5, and 10.0 cm did. Because 7.5 cm most closely approximates the mean renal cell cancer diameter as noted by SEER data, it is recommended that the TNM primary tumor cutoff be changed to 7.5 cm.

Carcinoma, Renal Cell↗