Background: Volatile organic compounds (VOCs) in urine may provide information about biomarkers of tumors in their early stages and about tumor growth. Methods: This study demonstrates that the effect of low protein diet on the pattern of VOCs in the urine of healthy and cancer bearing mice is significant. Results: Pentanal, found in nine out of the ten breast cancer-bearing mice on a high protein (HP) diet, was not found in any of the cancer bearing mice under a low protein (LP) diet, even after tumor development. In addition, the concentration of 3-heptanone, also elevated in the HP group, was not found in the LP group. Benzoic acid, 4-ethoxy-, ethyl ester, 2-pentanone, and propane, 1-isothiocyanato-3-(methylthio), all associated with anti-cancer properties or activity, were observed in the LP group, but not in the HP group. 6-methyl-3-heptanone exhibited a marked increase in concentration as a function of tumor growth when mice were maintained on an HP diet; however, its concentration exhibited no change in mice on the LP diet. The LP group showed much better survival, and even spontaneous recovery from cancer. Conclusion: Our results give an insight into the effects of an LP diet on the management of breast cancer and melanoma. While other research groups focus on improving the relative rates of efficacy and accuracy of cancer biopsy results, this study attempted to monitor the initial appearance of cancer by VOCs excreted in urine that may be associated with metabolic and other physiological changes associated with tumor development, and with a diet that inhibits such development.
The results suggest that the direct intratumoral insertion of a PdTMPyP4-containing polymeric rod would be of benefit as an adjuvant treatment for patients undergoing chemo- or radiotherapy. By preventing the lengthening of telomeres and therefore the unrestricted growth of cancer cells, our DDS will provide a significant therapeutic advantage to these treatments without affecting normal tissues.
This work offers an innovative technique to inhibit the activation of the telomerase enzyme over the long term and improve the outcome of cancer treatments. Telomerase activation elongates telomeres, sequences of DNA at the ends of chromosomes. This action confers unlimited proliferation on cancer cells and increases their resistance to chemo- and radio- therapy. Telomeres also lengthen when cells undergo homologous recombination via an Alternative Lengthening of Telomeres (ALT) pathway. Our technique embodies an effective drug delivery system (DDS) that maximizes tumor uptake of the inhibitor and provides its long term continuous release. This is accomplished by the direct, intratumoral insertion of a biodegradable polymeric rod incorporating a telomerase-inhibiting drug. Long-term continuous release of the drug is critical because, if the inhibitor is cleared from the tumor cell, telomerase is rapidly reactivated and the telomeres re-lengthen. The drug is a well-documented telomerase-inhibiting porphyrin (TMPyP4) that is incorporated into a Poly(Lactic-co-Glycolic) Acid (PLGA) polymer and inserted directly into anatomically-accessible tumors. The properties of TMPyP4 are retained even when the porphyrin is tagged with a stable palladium atom (Pd), PdTMPyP4. The molecule binds to, and influences the configuration of G-quadruplex (GQ) regions in DNA. GQs are located, among other sites, in the promoter region of the c-myc oncogene and in the telomeres. By stabilizing the promoter region of c-myc, PdTMPyP4 prevents its over-expression and stimulation of the human telomerase reverse transcriptase (hTERT), a subunit of telomerase, thereby inhibiting the activation of telomerase. The intratumoral insertion of the rod increases tumor-loading of the drug and permits the gradual and continuous release of PdTMPyP4 over the long term. ICP-MS measurements of Pd uptake in the DNA of Hodgkin's Lymphoma cells after a 24 or 48h incubation with PdTMPyP4 yielded >109 atoms/cell, and telomerase activity was significantly reduced as shown by the TRAP assay. Daily spectrophotometric measurements of the optical density (OD) of PdTMPyP4 shows its gradual and constant release from rods in vitro for 52 days and ex vivo for >30 days. The concentration of PdTMPyP4 released from the rods is proportional to the mass of the rods. After insertion of the rods into the KHJJ murine mammary adenocarcinoma borne on the BALB/c mouse thigh, tumor growth was 5-8 times slower than tumors without rods. Most importantly, based upon OD measurements of blood plasma, systemic uptake of PdTMPyP4 is negligible after intratumoral insertion of the rod into the KHJJ tumors. Each individual component of PdTMPyP4 independently challenges telomere elongation mechanisms. TMPyP4 inhibits telomerase, and the DNA-bound Pd atoms can be exploited to continuously fragment telomeres lengthened by ALT. The simultaneous or sequential intratumoral implantation of iodine-125 brachytherapy seeds and PdTMPyP4 rods, in a single treatment procedure, can produce clustered, non-repairable damage at all Pd-bound DNA sites due to the dense ionization of cascading Auger electrons. The 27 keV photon energies of iodine-125 seeds are ideally suited for inducing a photoelectric effect at the 24.5 K absorption edge of Pd, thereby eliciting the emission of low energy, short range Auger electrons over a sphere of 25 nm. Thus, the combined, but independent advantage of each molecular component, offers a potentially useful comprehensive therapeutic modality. Further, the intratumoral insertion of only the PdTMPyP4-releasing rod offers the potential of increasing the sensitivity of malignant tumors to conventional cancer treatments through telomerase inhibition. Conclusions reached thus far in our study strongly suggest that our technique for inhibiting the activation of telomerase has substantial utility for addressing a broad range of cancer types, such as prostate, breast, brain, and head and neck. This work offers an innovative technique to inhibit the activation of the telomerase enzyme over the long term and improve the outcome of cancer treatments. Telomerase activation elongates telomeres, sequences of DNA at the ends of chromosomes. This action confers unlimited proliferation on cancer cells and increases their resistance to chemo- and radio- therapy. Telomeres also lengthen when cells undergo homologous recombination via an Alternative Lengthening of Telomeres (ALT) pathway. Our technique embodies an effective drug delivery system (DDS) that maximizes tumor uptake of the inhibitor and provides its long term continuous release. This is accomplished by the direct, intratumoral insertion of a biodegradable polymeric rod incorporating a telomerase-inhibiting drug. Long-term continuous release of the drug is critical because, if the inhibitor is cleared from the tumor cell, telomerase is rapidly reactivated and the telomeres re-lengthen. The drug is a well-documented telomerase-inhibiting porphyrin (TMPyP4) that is incorporated into a Poly(Lactic-co-Glycolic) Acid (PLGA) polymer and inserted directly into anatomically-accessible tumors. The properties of TMPyP4 are retained even when the porphyrin is tagged with a stable palladium atom (Pd), PdTMPyP4. The molecule binds to, and influences the configuration of G-quadruplex (GQ) regions in DNA. GQs are located, among other sites, in the promoter region of the c-myc oncogene and in the telomeres. By stabilizing the promoter region of c-myc, PdTMPyP4 prevents its over-expression and stimulation of the human telomerase reverse transcriptase (hTERT), a subunit of telomerase, thereby inhibiting the activation of telomerase. The intratumoral insertion of the rod increases tumor-loading of the drug and permits the gradual and continuous release of PdTMPyP4 over the long term. ICP-MS measurements of Pd uptake in the DNA of Hodgkin's Lymphoma cells after a 24 or 48h incubation with PdTMPyP4 yielded >109 atoms/cell, and telomerase activity was significantly reduced as shown by the TRAP assay. Daily spectrophotometric measurements of the optical density (OD) of PdTMPyP4 shows its gradual and constant release from rods in vitro for 52 days and ex vivo for >30 days. The concentration of PdTMPyP4 released from the rods is proportional to the mass of the rods. After insertion of the rods into the KHJJ murine mammary adenocarcinoma borne on the BALB/c mouse thigh, tumor growth was 5-8 times slower than tumors without rods. Most importantly, based upon OD measurements of blood plasma, systemic uptake of PdTMPyP4 is negligible after intratumoral insertion of the rod into the KHJJ tumors. Each individual component of PdTMPyP4 independently challenges telomere elongation mechanisms. TMPyP4 inhibits telomerase, and the DNA-bound Pd atoms can be exploited to continuously fragment telomeres lengthened by ALT. The simultaneous or sequential intratumoral implantation of iodine-125 brachytherapy seeds and PdTMPyP4 rods, in a single treatment procedure, can produce clustered, non-repairable damage at all Pd-bound DNA sites due to the dense ionization of cascading Auger electrons. The 27 keV photon energies of iodine-125 seeds are ideally suited for inducing a photoelectric effect at the 24.5 K absorption edge of Pd, thereby eliciting the emission of low energy, short range Auger electrons over a sphere of 25 nm. Thus, the combined, but independent advantage of each molecular component, offers a potentially useful comprehensive therapeutic modality. Further, the intratumoral insertion of only the PdTMPyP4-releasing rod offers the potential of increasing the sensitivity of malignant tumors to conventional cancer treatments through telomerase inhibition. Conclusions reached thus far in our study strongly suggest that our technique for inhibiting the activation of telomerase has substantial utility for addressing a broad range of cancer types, such as prostate, breast, brain, and head and neck. Citation Format: Brenda Laster, Carol Isaacson, Ekaterina Perets, Maha Msamra, Esther Priel, John Kalef-Ezra, Joseph Kost. An innovative technique for preventing telomere elongation and its associated immortalization of cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B50.
Purpose: To improve prostate‐cancer imaging by making use of independent prostate tissue properties sensed by multiple imaging modalities such as the choline‐to‐citrate ratio detected by magnetic‐resonance (MR) spectroscopy in conjunction with parameters of ultrasound (US) echo‐signal spectra and clinical variables. Method and Materials: Ultrasonic (US) radio‐frequency (RF) echo‐signal data, and clinical variables including prostate‐specific antigen (PSA), were acquired during biopsy examinations. A neural‐network classifier was trained using spectral parameters computed from the RF data. Biopsy‐core histology was used as the gold standard. Classifier performance was assessed using ROC analysis. A look‐up table that returned cancer‐likelihood scores for spectral parameter and PSA combinations was used to generate tissue‐type images (TTIs). 3‐D renderings of the prostate were generated from transverse MR and US scans to determine feasibility of combining the two imaging modalities. The MR 3‐D volume was warped in 3‐D using the US volume as a reference to compensate for the distortions introduced by the larger endorectal probe used in MR imaging. Results: The ROC‐curve area for US neural‐network‐based classification was 0.84 compared to the ROC‐curve area of 0.64 for B‐mode based classification. Cancerous regions that were not visible in conventional US images were revealed in the TTIs. Co‐registration of 3‐D prostate phantom US and MR images after warping was successful. Conclusions: TTIs based on neural‐network classification of US and clinical parameters show promise for improving the detection of prostate cancer. Warping 3‐D renderings of the prostate to compensate for the deformations introduced by different probes appears to be feasible. Consequently, we will be able to produce accurately co‐registered 3‐D data derived from US and MR to improve methods for visualizing prostate‐cancer foci. Success in combining the two imaging modalities will be valuable for depicting cancerous regions in the prostate for biopsy and treatment planning and treatment monitoring.
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