Steven H. Selman

Why drinking green tea could prevent cancer

Epidemiological studies suggest that the consumption of green tea may help prevent cancers in humans; also, breast and prostate cancers in animal models are reduced by green, but not black, tea. Here we offer a possible explanation. We have inferred (using molecular modelling) and subsequently demonstrated that one of the major ingredients of green tea inhibits urokinase, an enzyme crucial for cancer growth.

Effects of tacrolimus on hyperlipidemia after successful renal transplantation: A southeastern organ procurement foundation multicenter clinical study

BACKGROUND Tacrolimus has been shown to have a less adverse effect on the lipid profiles of transplant patients when the drug is started as induction therapy. In order to determine the effect tacrolimus has on lipid profiles in stable cyclosporine-treated renal transplant patients with established hyperlipidemia, a randomized prospective study was undertaken by the Southeastern Organ Procurement Foundation. METHODS Patients of the 13 transplant centers, with cholesterol of 240 mg/dl or greater, who were at least 1 year posttransplant with stable renal function, were randomly assigned to remain on cyclosporine (control) or converted to tacrolimus. Patients converted to tacrolimus were maintained at a level of 5-15 ng/ml, and control patients remained at their previous levels of cyclosporine. Concurrent immunosuppressants were not changed. Levels of total cholesterol, triglycerides, total high-density lipoprotein, low-density lipoprotein (LDL), very-low-density lipoprotein, and apoproteins A and B were monitored before conversion and at months 1, 3, and 6. Renal function and glucose control were evaluated at the beginning and end of the study (month 6). RESULTS A total of 65 patients were enrolled; 12 patients failed to complete the study. None were removed as a result of acute rejection or graft failure. Fifty-three patients were available for analysis (27 in the tacrolimus group and 26 controls). Demographics were not different between groups. In patients converted to tacrolimus treatment, there was a -55 mg/dl (-16%) (P=0.0031) change in cholesterol, a -48 mg/dl (-25%) (P=0.0014) change in LDL cholesterol, and a -36 mg/dl (-23%) (P=0.034) change in apolipoprotein B. There was no change in renal function, glycemic control, or incidence of new onset diabetes mellitus in the tacrolimus group. CONCLUSION Conversion from cyclosporine to tacrolimus can be safely done after successful transplantation. Introduction of tacrolimus to a stable renal patient does not effect renal function or glycemic control. Tacrolimus can lower cholesterol, LDL, and apolipoprotein B. Conversion to tacrolimus from cyclosporine should be considered in the treatment of posttransplant hyperlipidemia.

MORPHOLOGICAL CHANGES OF TUMOR MICROVASCULATURE FOLLOWING HEMATOPORPHYRIN DERIVATIVE SENSITIZED PHOTODYNAMIC THERAPY

Abstract There is increasing evidence that the tumor microvasculature is affected during porphyrin photodynamic therapy. In the following study, the effect of hematoporphyrin derivative photodynamic therapy on tumor microvasculature was studied by electron microscopy. Urothelial tumors, implanted subcutaneously in rats, were exposed to red light (> 590 nm; 360 J cm−2) 72 h after injection of hematoporphyrin derivative at a dose of 5 mg kg−1 of body weight. Prior to sampling, in vivo perfusion was carried out using a polyvalent cation, lanthanum, in 3% glutaraldehyde to define the endocapillary layer of endothelial cells. Samples of tumors were collected at 0, 1,2 and 4 h after completion of photodynamic therapy. Histological changes in endothelial cells were evident immediately following completion of light exposure. Immediate morphological changes included absence of the endocapillary layer as well as mitochondrial degeneration. The changes within tumor cells followed the changes within the microvasculature. This study indicates that the endothelial cell of tumor tissue is an important target of photodynamic therapy and may be responsible for the blood flow changes reported previously.

Photodynamic Treatment of Transplantable Bladder Tumors in Rodents After Pretreatment with Chloroaluminum Tetrasulfophthalocyanine

Chloroaluminum tetrasulfophthalocyanine (AlPCS) was used as a photosensitizer for the photodynamic treatment of transplantable N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) induced urothelial tumors. Two groups of six rats each were injected with AlPCS (three micrograms./gm. body weight) and 24 hours after injection underwent photodynamic treatment with red light (greater than 590 nm., 360 joules/cm.2). Tumors examined four hours (Group I) and 24 hours (Group II) after the completion of phototreatment showed extensive hemorrhagic necrosis. Tumors treated with AlPCS alone showed no changes. In two other groups of six rats each, blood flow to tumors treated with AlPCS alone (Group III) and AlPCS plus light (Group IV) was measured using the radioactive microsphere technique. AlPCS plus light resulted in a significant decrease (p less than .05) in tumor blood flow within 10 minutes of completion of phototreatment while AlPCS alone had no effect on tumor blood flow. These findings are similar to those observed when higher doses (10 micrograms./gm. to 20 micrograms./gm. body weight) of hematophorphyrin derivative (HpD) and light were used for phototreatment of FANFT induced tumors. AlPCS is a stable sulfonated derivative of tetraazotetrabenzoporphyrin which absorbs maximally in the red portion of the visible spectrum, a region with good tissue penetration properties. These studies suggest the AlPCS may be a useful new agent for photodynamic therapy of cancer.

Diverse optical characteristic of the prostate and light delivery system: implications for computer modelling of prostatic photodynamic therapy

To explore the use of photodynamic therapy (PDT) as a minimally invasive form of treatment for organ‐confined prostate cancer, for although there are several therapies, ablative treatments are associated with significant morbidity.

Transperineal Photodynamic Ablation of the Canine Prostate

PURPOSE Experiments were undertaken to determine the effects of transperineal interstitial photodynamic therapy on the canine prostate. MATERIALS AND METHODS Mongrel dogs were injected intravenously with the photosensitizer, tin (II) ethyl etiopurpurin dichloride. Twenty-four hours later, 2 optical fibers were implanted in 1 hemisphere of the prostate, which was then treated with red light (660 nm.). RESULTS Acutely, the treated areas showed extensive hemorrhagic necrosis. At 3 and 6 weeks, the treated lobes were largely replaced by fibrous connective tissue. CONCLUSION Transperineal photodynamic therapy of the canine prostate is feasible. Further preclinical investigation is warranted to determine the applicability of this approach to the treatment of localized prostate cancer.

Synthetic curcuminoids modulate the arachidonic acid metabolism of human platelet 12-lipoxygenase and reduce sprout formation of human endothelial cells

Platelet 12-lipoxygenase (P-12-LOX) is overexpressed in different types of cancers, including prostate cancer, and the level of expression is correlated with the grade of this cancer. Arachidonic acid is metabolized by 12-LOX to 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], and this biologically active metabolite is involved in prostate cancer progression by modulating cell proliferation in multiple cancer-related pathways inducing angiogenesis and metastasis. Thus, inhibition of P-12-LOX can reduce these two processes. Several lipoxygenase inhibitors are known, including plant and mammalian lipoxygenases, but only a few of them are known inhibitors of P-12-LOX. Curcumin is one of these lipoxygenase inhibitors. Using a homology model of the three-dimensional structure of human P-12-LOX, we did computational docking of synthetic curcuminoids (curcumin derivatives) to identify inhibitors superior to curcumin. Docking of the known inhibitors curcumin and NDGA to P-12-LOX was used to optimize the docking protocol for the system in study. Over 75% of the compounds of interest were successfully docked into the active site of P-12-LOX, many of them sharing similar binding modes. Curcuminoids that did not dock into the active site did not inhibit P-12-LOX. From a set of the curcuminoids that were successfully docked and selected for testing, two were found to inhibit human lipoxygenase better than curcumin. False-positive curcuminoids showed high LogP (theoretical) values, indicating poor water solubility, a possible reason for lack of inhibitory activity or/and nonrealistic binding. Additionally, the curcuminoids inhibiting P-12-LOX were tested for their ability to reduce sprout formation of endothelial cells (in vitro model of angiogenesis). We found that only curcuminoids inhibiting human P-12-LOX and the known inhibitor NDGA reduced sprout formation. Only limited inhibition of sprout formation at ∼IC50 concentrations has been seen. At IC50, a substantial amount of 12-HETE can be produced by lipoxygenase, providing a stimulus for angiogenic sprouting of endothelial cells. Increasing the concentration of lipoxygenase inhibitors above IC50, thus decreasing the concentration of 12(S)-HETE produced, greatly reduced sprout formation for all inhibitors tested. This universal event for all tested lipoxygenase inhibitors suggests that the inhibition of sprout formation was most likely due to the inhibition of human P-12-LOX but not other cancer-related pathways. [Mol Cancer Ther 2006;5(5):1371–82]

STUDIES OF TIN ETHYL ETIOPURPURIN PHOTODYNAMIC THERAPY OF THE CANINE PROSTATE

PURPOSE Previous studies have demonstrated the technical feasibility of destroying prostate tissue using photodynamic therapy for benign and malignant disease. A series of canine studies was performed to evaluate the systemic uptake and distribution of the photosensitizer tin ethyl etiopurpurin (SnET2) in the prostate and surrounding tissues, and determine the optimal combination of drug dose, light dose and time interval between drug and light administration using transurethral and transperineal interstitial light delivery. MATERIALS AND METHODS Adult male mongrel source dogs received intravenous bolus injections of 0.5 or 1.0 mg./kg. SnET2 in 4 studies. In the first study the concentration of SnET2 in the prostate and surrounding tissue was measured at various time points after dosing. In the second study a tissue dose response relationship of SnET2-PDT was studied after transperineal interstitial light application. The third and fourth studies evaluated the tissue effects of combined transurethral and transperineal interstitial light application on SnET2 sensitized prostates. RESULTS Substantial amounts of SnET2 were measured in the prostate between 24 and 168 hours after infusion. Drug and light dose dependent prostatic tissue necrosis and volume reduction were documented in the dose response relationship study. The combination of transurethral and transperineal light resulted in the extensive destruction of glandular epithelium with minimal damage to surrounding structures. Average prostate volume decreased 52%. Transperineal interstitial light delivery with multiple diffusers resulted in substantial glandular destruction of the prostate. An average volume reduction of more than 60% was achieved. CONCLUSIONS SnET2-PDT is a viable minimally invasive treatment modality for prostate tissue destruction.

CURCUMIN PREVENTS INTRAVESICAL TUMOR IMPLANTATION OF THE MBT-2 TUMOR CELL LINE IN C3H MICE

PURPOSE The development of an effective nontoxic intravesical agent that may be used immediately after bladder tumor resection to prevent the implantation of tumor cells would be a significant clinical advancement. We report the cytotoxic effects of curcumin on bladder tumor cell lines as well as its effects on the intravesical implantation of tumor cells in C3H mice. MATERIALS AND METHODS UMUC human and MBT-2 mouse bladder cancer lines were incubated with 0 to 100 microM. curcumin in dimethyl sulfoxide for 30 minutes and cell viability was determined by clonal assay. Additional culture dishes were incubated with curcumin and processed for electron microscopy. Using the C3H mice and the MBT2 tumor lines the effects of intravesical curcumin on tumor implantation after bladder injury was studied. The 10 group 1 mice served as nontreatment controls. In the 18 group 2 mice 30 minutes after tumor cell implantation 100 microM. curcumin in 0.1% dimethyl sulfoxide were instilled intravesically for 30 minutes. The 15 group 3 mice served as treatment controls with 0.1% dimethyl sulfoxide or culture medium instilled intravesically for 30 minutes. Animals were sacrificed 7 to 10 days after treatment and the bladder was subjected to histological analysis for tumor. RESULTS At the 100 microM. dose curcumin was completely lethal to the 2 cell lines on clonal growth assay. Electron microscopy revealed apoptotic bodies after curcumin administration. The tumor implantation rate was 16.7% (3 of 18 mice) in curcumin treated bladders and 73% (11 of 15) in the vehicle control group. CONCLUSIONS At the 100 microm. concentration curcumin is a potent cytotoxic agent against the MBT and UMUC bladder tumor cell lines. In addition, curcumin effectively inhibits tumor implantation and growth in this murine bladder tumor model.

METALLOPURPURINS and LIGHT: EFFECT ON TRANSPLANTABLE RAT BLADDER TUMORS and MURINE SKIN

Purpurins are modified chlorins with photodynamic properties. Their strong absorption in the red region of the visible spectrum makes them candidates for use in photodynamic cancer therapy. A series of metal derivatives of the free base purpurins have been synthesized and shown to cause tumor necrosis in transplantable tumors when exposed to visible light. In the following set of experiments, the effects of two metallo‐derivatives (tin and zinc) of two purpurins, octaethylpurpurin (NT2) and etiopurpurin (ET2), and light on the N‐{4‐(5‐nitro‐2‐furyl)‐2‐thiazolyl}formamide transplantable tumors in Fischer CDF(F344)/CrlBr rats were studied. The photodynamic activity was assessed by a short term assay using tumor dry weight 12 days after purpurin‐PDT as a criterion of response. From these experiments it appears that SnET2>SnNT2>ZnET2>ZnNT2 in photodynamic activity. SnET2 was further characterized by attempting to determine the time interval after systemic injection at which maximum therapeutic effect occurred. These studies shown that 24 h after metallopurpurin injection was the optimum time for treatment of tumors with visible light. In a final set of experiments, the effect of solar light on the skin of hairless mice injected with SnET2 was found to be much less injurious than with hematoporphyrin derivative.