Biomedical subjects

R E Saxton

Publications and source records attributed to R E Saxton.

At least 19 recordsLinked to original sources

PubMed2000

Hypericin and photodynamic therapy decreases human pancreatic cancer in vitro and in vivo.

BACKGROUND: The treatment of pancreatic cancer has remained dismal despite advances in medical and surgical care. Recent preclinical data have revealed that hypericin, a photochemical dye, is activated by green light and generates toxic radical species in tumors. We hypothesized that interstitial hypericin and laser phototherapy would decrease pancreatic cancer growth. METHODS: MiaPaCa-2 and PANC-1 cells were grown in tissue culture. In vitro experiments were performed with addition of 10 microg of hypericin/500,000 cancer cells. Cells were incubated with hypericin for 2 h. Cells were then exposed to KTP532 green laser light for 1 min at 0.6 W using a cylindrical diffuser tip. Cell growth was measured by MTT assay 24 h after laser treatment, N = 12. MiaPaCa-2 cells were implanted subcutaneously and orthotopically in pancreas of nude mice. After 5 weeks, both tumors were injected with 100 microg of hypericin followed by insertion of a cylindrical diffuser tip into the tumor center. Mice received 200J KTP laser light at 1.0 W in two sites. Tumors were measured before and 4 weeks after laser treatment. RESULTS: Both in vitro and in vivo mice data showed a significant decrease in growth of pancreatic cancer. Pancreatic cancer cell growth was suppressed by 66.1 +/- 0.2%, n = 12, P < 0.01, ANOVA. Subcutaneous shoulder tumors were suppressed by 91.2 +/- 2.3%, n = 12, P < 0.001, and orthotopically grown pancreatic tumors were suppressed by 42.2 +/- 8.1%, n = 12, P < 0.05, compared to pretreatment sizes. Data expressed as percentage reduction vs paired controls in the MTT assay and vs pre-photodynamic therapy in mice experiments. Paired Student's t tests were performed vs pretreatment sizes. CONCLUSION: Both in vitro and in vivo results revealed a significant decrease in pancreatic cancer cell growth. Laser or dye alone had no effect, indicating that intratumor hypericin and laser therapy may prove useful in unresectable pancreatic cancer.

Animals↗

PubMed2000

Intratumoral hypericin and KTP laser therapy for transplanted squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: To test intratumoral photodynamic therapy (IPDT) as a new treatment for squamous cell carcinoma in a preclinical tumor model. STUDY DESIGN AND METHODS: Human P3 squamous carcinoma cells were transplanted subcutaneously in athymic nude mice and allowed to grow into 300- to 500-mm3 tumors. Hypericin dye at 1 microg/gm of body weight was injected intratumorally (IT) or intravenously (IV). After 4 hours hypericin biodistribution was assessed in ethanol extracts from tissues by fluorescence spectroscopy. IPDT also was tested by KTP laser fiberoptic insertion in tumors 4 hours after IT dye injection compared to KTP532 laser therapy alone (532 nm, 1W, 40-60 J, 0.6-mm fiber). RESULTS: Hypericin concentration in tissues was as follows: (IT vs. IV) for tumors (3660 vs. 135 ng dye/gm tissue), lung (760 vs. 6345), liver (75 vs. 935), blood (65 vs. 480) compared to skin (465 vs. 110) or muscle (335 vs. 80) adjacent to the squamous cell tumors. Four hours after dye injection, the tumor exhibited bright orange fluorescence when excited by KTP 532-nm green laser light. The IPDT-treated tumors had a 3.32+/-0.32-mm radius of cell destruction when H&E-stained sections were examined compared with 2.5+/-0.38 mm for the laser only control group (n = 10, P = .003). CONCLUSIONS: This pilot study indicates laser IPDT with hypericin induces a significant increase in tumor necrosis compared with laser alone and may be useful as a less invasive adjuvant treatment for recurrent or inoperable human squamous cell cancers of the head and neck.

Animals↗

PubMed1999

MRI of thermally denatured blood: methemoglobin formation and relaxation effects.

Focal regions of T1-shortening have been observed in magnetic resonance imaging (MRI)-monitored thermal ablations of perfused tissues. The aims of this study were two-fold: to find evidence for heat-induced conversion of hemoglobin (Hb) to methemoglobin (mHb), and to investigate the effects of heat treatment of in-vitro blood components upon their MR relaxation times. Spectrophotometric studies were performed to confirm the heat-induced formation of methemoglobin. Preparations of whole and fractionated blood, previously submitted to elevated temperatures of 40 degrees C to 80 degrees C, were imaged and the relaxation times were calculated. Optical absorption spectra of samples containing free Hb, heated to 60 degrees C, showed increased light absorption at 630 nm, evident of mHb presence. Short T1 values in whole blood (1.13 s) and packed red blood cell (0.65 s) compartments, heated at 60 degrees C, compared to their baseline values (1.62 s and 0.83 s, respectively), were attributed to mHb formation. In relation to MRI-guided thermal interventions, these results suggest a possible explanation for observation of hyperintense regions on T1-weighted images.

Animals↗

PubMed1999

Combined intratumor cisplatinum injection and Nd:YAG laser therapy.

OBJECTIVES/HYPOTHESIS: Interstitial laser therapy (ILT) has become useful for tumor palliation in patients with advanced head and neck cancer. Cisplatinum chemotherapy also is a frequent adjuvant treatment for recurrent tumors, but systemic toxicity limits application. Intratumor cisplatinum injection combined with ILT may improve therapy of these recurrent tumors with reduced toxicity. STUDY DESIGN: Prospective. Tumor transplants were injected with cisplatinum in a gel implant before ILT to evaluate treatment response and toxicity in a preclinical study. METHODS: UCLA-P3 human squamous cell carcinoma tumors were grown as subcutaneous transplants in nude mice and treated by intratumor injection of 2 mg/mL cisplatinum in a slow-release, collagen-based gel carrier 4 hours before interstitial implantation of Nd:YAG laser fiberoptics to induce local tumor hyperthermia. Treatment efficacy and toxicity were followed for 12 weeks after combined drug and laser therapy compared with ILT alone. RESULTS: Combined cisplatinum gel and ILT was a significant improvement (P < .01 by chi-square test) and induced 57% complete responses without regrowth in 21 transplanted tumors compared with only 24% in 21 tumors after ILT alone during 12-week follow-up. Recurrences in both cases appeared to result from nonuniform laser energy delivery within tumors via the implanted fiberoptic tip. CONCLUSIONS: The results of this experimental combined cisplatinum and ILT study suggest it may be possible to improve treatment of advanced head and neck cancer by intratumor injection of gel implants containing the drug followed by interstitial Nd:YAG laser hyperthermia.

Animals↗

PubMed1998

Improved photochemotherapy of malignant cells with daunomycin and the KTP laser.

Laser photochemotherapy of malignancies may become an effective palliative treatment for advanced had and neck cancer using light-sensitive, chemotherapeutic drugs activated in tumors via interstitial laser fiberoptics. Previously, it was reported that cultured human P3 squamous cells incubated 2 hours with daunomycin (Dn) exhibited tenfold enhanced cytotoxicity after exposure to argon laser light at 514 nm. This short-term uptake leads to drug localization in cytoplasmic and membrane sites prior to nuclear accumulation and daunomycin topoisomerase inhibition. In the current study phototoxicity of Dn-sensitized human cancer cells was tested using broad-spectrum white light compared to monochromatic green-wavelength light. Drug uptake and laser energy levels were optimized for maximum synergy. To test light-enhanced chemotherapy in vitro, the kinetics of cell uptake and toxicity of daunomycin was measured at 1, 2, and 5 microg/ml in three human tumor cell lines: P3 squamous-cell carcinoma, M26 melanoma, and TE671 fibrosarcoma. After 2 hr Dn uptake, all cell lines were tested for phototherapy response by exposure to 300- to 900-nm visible light from a xenon lamp or monochromatic 532-nm green light from a KTP laser. When the KTP laser output was varied from 0 to 120 Joules in Dn-sensitized tumor cells, a linear phototherapy response was seen with energy as low as 12 J inducing drug phototoxicity. These results provide evidence that daunomycin cytotoxicity is enhanced when exposed to 532-nm laser illumination in the three tumor types tested and confirm that the response is related to both energy level and drug dose.

Carcinoma, Squamous Cell↗

PubMed1998

Anthrapyrazoles and interstitial laser phototherapy for experimental treatment of squamous cell carcinoma.

Interstitial laser therapy (ILT) is an effective palliative treatment for advanced head and neck cancer, but recurrence often is seen at the margin. The objective of the current study was to test combined drug and laser therapy as an experimental approach for improved treatment of human squamous cell carcinoma (SCCA). Human SCCA tumor transplants were grown in nude mice and injected with the photosensitive anthrapyrazole CI-941 before ILT. Intralesional drug injections alone at levels ranging from 60 to 1200 microg/gm of tumor induced a growth delay at the higher doses, but recurrence was seen in all 35 tumors tested. SCCA tumor transplants injected with 240 microg/gm CI-941 followed after 4 hours by ILT with the KTP532 laser led to a complete response rate of 72% (21/29) compared with 45% (13/29) for ILT alone. Laser chemotherapy was a significant improvement compared with ILT when partial and complete responses were combined (P < 0.03). The results provide preclinical evidence that laser chemotherapy may become a useful minimally invasive treatment for advanced squamous cell carcinoma of the head and neck.

Animals↗

PubMed1998

Laser and cisplatinum for treatment of human squamous cell carcinoma.

OBJECTIVE: Interstitial laser therapy (ILT) with the neodymium:yttrium-aluminum-garnet (Nd:YAG) (1064 nm) laser via fiberoptics is becoming a more precise, minimally invasive alternative for thermoablation of unresectable or recurrent head and neck neoplasms, but recurrence is often seen at the margin. Combining intratumor chemotherapy with interstitial laser should be most effective using drugs activated by thermal energy. The objective of the current study was to test intratumor cisplatinum (cis-diaminedichloroplatinum [CDDP]) injections given in conjunction with laser therapy as an experimental approach for improved treatment of squamous cell carcinoma (SCC). METHODS: Human SCC tumors were grown as subcutaneous transplants in nude mice and injected with CDDP (0.4 to 1.2 mg/g) in water or in collagen-based gel carrier with epinephrine (epi-gel) followed by ILT via 0.6-mm fiberoptics coupled to an Nd:YAG laser (1064 nm/180 J). RESULTS: Tumors injected with CDDP epi-gel exhibited a partial response with two- to fourfold tumor delay compared with aqueous drug or untreated SCC transplants during 10 weeks' follow-up. Combined drug and laser therapy significantly (P < .01) decreased tumor volume, with recurrence in only 25% of animals tested compared with 78% tumor regrowth after ILT alone. CONCLUSION: These initial results suggest that laser chemotherapy may become an effective treatment for advanced head and neck cancer.

Animals↗

PubMed1998

Palliative laser therapy for recurrent head and neck cancer: a Phase II clinical study.

OBJECTIVES: Laser therapy is becoming a more precise, minimally invasive alternative for tumor ablation. Recent reports confirm successful palliation of pain and functional disabilities in patients with advanced deep carcinoma of the head and neck using interstitial laser phototherapy (ILT). STUDY DESIGN, PATIENTS, AND METHODS: The current study describes an ongoing Phase II trial of neodymium/yttrium-aluminum-garnet (Nd:YAG) laser therapy for palliation of advanced head and neck cancer. A total of 40 advanced cancer patients have been entered into this protocol (25 men and 15 women). RESULTS: Nineteen of these patients had no evidence of recurrence after ILT with an average follow-up of 11 months (range, 2 to 24 mo). Currently, 19 of these patients are alive, 14 with tumor remission and six with persistent disease. A total of 79 tumor sites received ILT with 43 (54.5%) completely ablated. Stratified by tumor site, ILT led to a complete response in 21 of 24 in the oral cavity, eight of 28 neck tumors, four of 10 in skin, and 10 of 17 in other sites. The procedure was well tolerated in most cases and was repeated at intervals in patients with residual disease or recurrences for a total of 118 laser treatments (average, 2.95 treatments per patient). CONCLUSIONS: The results suggest that ILT can be performed safely and repeated as needed, and may be less costly than conventional surgery for head and neck cancer. However, additional follow-up is needed to obtain convincing evidence of long-term therapeutic benefits.

Adult↗

PubMed1997

Cisplatinum and interstitial laser therapy for advanced head and neck cancer: a preclinical study.

BACKGROUND AND OBJECTIVE: Direct intratumor injection of cisplatinum (CDDP) and laser therapy were tested for improved treatment of squamous cell carcinoma (SCCA). STUDY DESIGN/MATERIALS AND METHODS: Human SCCA tumors were grown as s.c. transplants in nude mice and injected with CDDP (0.4-1.2 mg/gm) in water or in collagen-based gel carrier with epinephrine (epi-gel), followed by interstitial laser therapy (ILT) via 0.6 mm fiberoptics (532 nm/300 J). RESULTS: Tumors injected with CDDP epi-gel exhibited a partial response with 2-4-fold tumor growth delay, compared to aqueous drug or untreated SCCA transplants during 10-week follow-up. Combined drug and laser therapy significantly decreased tumor volume with recurrence in only 25% (2/8) of animals tested, compared to 66% tumor regrowth (10/15) after ILT alone. CONCLUSION: These initial results suggest laser chemotherapy may become an effective treatment for advanced head and neck cancer.

Animals↗

PubMed1997

Laser chemotherapy of human carcinoma cells with three new anticancer drugs.

A new experimental therapy for squamous carcinoma was tested by sensitizing human tumor cells with light-sensitive anticancer drugs followed by laser illumination at visible or infrared wavelengths. The anthrapyrazole DUP-941 and the isoquinoline derivative DUP-840 were compared with the dianthraquinone hypericin. P3 human squamous carcinoma cells were incubated for 2 h with the drugs at escalating doses ranging from 5 to 100 micrograms/ml, then exposed to visible green 532-nm or infrared 1064-nm light at 300 J output from a KTP/Nd:YAG laser. Tumor cell toxicity measured by in vitro MTT viability assays was minimal after DUP-840 uptake but was slightly enhanced by infrared laser emissions. By contrast, the strong tumoricidal effects seen after DUP-941 uptake were amplified over 10-fold by 532-nm light and up to 2-fold by 1064-nm light. Hypericin-sensitized tumor cells were killed after 532 nm irradiation even at the lowest drug dose but were not affected by 1064-nm illumination. The results suggest that laser chemotherapy with drugs sensitive to photothermal energy could become a useful new treatment modality for cancer.

Anthracenes↗

PubMed1997

KTP laser and neutral red phototherapy of human squamous cell carcinoma.

Neutral red (NR) is a cationic, nontoxic vital dye employed as a histologic stain for proliferating cells; it has been used clinically for photodynamic treatment of herpes simplex virus lesions. NR is selectively taken up and concentrated by mitotic cells, an important characteristic for more effective antineoplastic agents. In the present study, UCLA-SO-P3 human squamous carcinoma cells displayed minimal toxicity when incubated with up to 50 microg/ml NR in the absence of light. However, cells incubated with greater than 0.5 microg/ml NR followed by exposure to KTP laser light at 532 nm exhibited nearly 100% tumor cell death. The degree of cell toxicity was proportional to NR dose and laser light fluence. This study demonstrates that NR is an excellent cancer cell photosensitizer in vitro, and, after adding additional in vivo preclinical testing, may prove to be a useful agent in photodynamic destruction of head and neck tumors.

Antineoplastic Agents↗

PubMed1996

MRI-guided laser interstitial thermal therapy (LITT) of head and neck tumors: progress with a new method.

A less invasive method for treatment of tumors is being tested based on interstitial photothermal ablation via infrared Nd:YAG laser fiber optics. The technique can be applied safely and effectively for therapy of common tumors in humans. In the current study five patients were treated by interstitial laser palliation with the Nd:YAG laser using special fiberoptic applicator tips, which distribute laser energy efficiently throughout the tumor volume. Magnetic resonance imaging (MRI) scanning was employed to locate the tumor, position the fibers correctly, and monitor the development of thermal necrosis in the tumors. Two patients were diagnosed with adenoid cystic carcinoma of the paranasal sinuses, one with a recurrent carcinoma of the tongue and oropharynx, one with a recurrent carcinoma limited to the oropharynx, and one patient with a carcinoma of the epi- and oropharynx. The maximum follow-up without recurrence was 2 years in a patient with an adenoid cystic carcinoma tumor of the paranasal sinuses. There were no immediate or delayed complications. Anatomical structures including eyes, brain, and important vessels were recognized by MRI during laser therapy. MRI-guided interstitial laser photothermal ablation appears to be a safe and effective method for treatment of selected tumors of the head and neck region with particular applications in palliation of inoperable tumor recurrences.

Aged↗

PubMed1996

Laser photochemotherapy with anthracyclines on cultured human squamous carcinoma cells.

A new treatment for cancer has been tested in vitro using light-sensitive anthracyclines followed by laser photoactivation, as described by several investigators. We previously reported 10-fold enhanced laser killing after 2 hours of incubation with daunomycin by cultured human carcinoma cells. This short-term uptake leads to drug localization in cytoplasmic and membrane sites prior to nuclear accumulation and topoisomerase inhibition. In the present study, daunomycin was incubated for 2 or 24 hours with P3 squamous carcinoma cells to directly compare cytoplasmic vs. nuclear drug targeting before and after KTP-532 laser activation. Monolayer cultures of the P3 cells sensitized with daunomycin for 2 hours, then chilled (4 degree C), and exposed to the KTP laser (532 nm, 94.2 J/cm2) had a 2- to 10-fold increased therapeutic response compared with drug or laser alone when measured by MTT tetrazolium assays. After 24 hours of incubation with daunomycin, the chemotherapeutic response of P3 tumor cells was amplified 2-fold by laser exposure. The results suggest that daunomycin and laser treatment can be combined for improved therapy of human cancer.

Antibiotics, Antineoplastic↗

PubMed1996

Hypericin: a new laser phototargeting agent for human cancer cells.

Laser activation of anthracycline-related drugs combines chemotherapy with photoablation for improved treatment. Hypericin, a structurally related anthraquinone, was tested for laser activation and cytotoxicity in human cancer cells. Viability of P3 squamous cell carcinoma cells incubated with 1 to 20 microgram/mL hypericin was reduced by more than 95% after 1 minute exposure at 4 degrees C to an argon laser (514 nm, 5 W), a KTP-532 laser (532 nm, 5 W), or a 20-A xenon lamp. Viability was reduced over 90% in six human carcinoma, sarcoma, and melanoma cell lines by this combined treatment, but only trace toxicity was seen after separate exposure to hypericin or light alone. These results show that hypericin is a sensitive agent for phototherapy of human cancer cells in vitro and indicate that this drug may be useful for tumor targeting via minimally invasive imaging-guided laser fiber optics.

Anthracenes↗

PubMed1996

The concept of laser phototherapy.

Laser phototherapy and diagnosis are emerging as new tools for cancer detection and treatment. Tumor uptake of laser dyes and chemotherapy drugs followed by laser fiberoptic insertion provides a less invasive and more effective treatment option for many cancer patients. Further development will be needed to identify optimal drug and laser combinations before this new approach becomes clinically useful.

Antineoplastic Agents↗

PubMed1995

Human pancreatic cancer growth is inhibited by peptide YY and BIM-43004-1.

Exogenous peptide YY (PYY) decreases pancreatic exocrine secretion, pancreatic endocrine function, and pancreatic blood flow. We hypothesized that pancreatic cancer cell growth may be inhibited by PYY and a new synthetic analog, BIM-43004-1. Two human pancreatic ductal adenocarcinomas, PANC-1 and Mia PaCa-2, were examined in tissue cultures. Viable pancreatic cancer cells were counted with trypan blue on a hemocytometer slide. Cells (10K, 20K, 40K, and 80K) were cultured and allowed to grow for 36 hr (n = 14/cell concentration). Pancreatic cancer cells received either PYY or BIM-43004-1 at various concentrations. Control tissue cultures received an equivalent volume of saline inoculation. After incubation with the above peptides for 24 hr, MTT tetrazolium bromide was added to assay mitochondrial activity of pancreatic cancer cells in response to PYY and its analog. MTT assay reveals a significant decrease in pancreatic cancer cell growth when PYY and BIM-43004-1 are added to the cell culture. Results in Mia PaCa-2 reveal a 24% cell growth reduction after exposure to PYY and a 23% reduction in cell growth when treated with BIM-43004-1. In PANC-1 cells, a 25% reduction in growth of cells is noted after PYY treatment and a 24% reduction in growth after BIM-43004-1 treatment. (means +/- SEM, P < 0.05 by Student's t test). Our results reveal a significant reduction in human ductal pancreatic cancer growth when treated with either PYY or its analog, BIM-43004-1. These agents may be useful hormonal adjuncts in the chemotherapy of pancreatic adenocarcinoma.

Cyclic AMP↗

PubMed1995

Y2 receptors decrease human pancreatic cancer growth and intracellular cyclic adenosine monophosphate levels.

BACKGROUND: Peptide YY (PYY), a 36 amino acid enteric hormone, is known to decrease pancreatic exocrine and endocrine function. Previous studies with BIM-43004-1, a modified PYY(22-36) Y2 receptor agonist, have revealed diminished mitochondrial activity in pretreated pancreatic cancer cells in vitro. We investigated the effects of both PYY and BIM-43004-1 on pancreatic cancer growth in vivo. METHODS: The 100,000 to 150,000 human pancreatic cancer cells, Mia PaCa-2, were orthotopically transplanted into 48 male athymic mice. After 1 week animals were treated with either PYY or BIM-43004-1 at 200 pmol/kg/hr via miniosmotic pumps for 2, 3, or 4 weeks. Paired controls received saline solution. At death tumor size and mass were measured. Receptor binding studies and intracellular cyclic adenosine monophosphate (cAMP) levels were measured in vitro. RESULTS: All mice had significant human cancer growth within the pancreas by histologic sections at 2, 3, and 4 weeks. Tumor mass was decreased by 60.5% in BIM-43004-1 treated mice and 27.1% in PYY treated mice. Receptor binding studies revealed binding of [125I]-BIM-43004-1 and displacement of ligand on competitive addition of nonradioactive BIM-43004-1. K dissociation constant of 4.5 nmol and 27,000 receptors per cell were quantitated by receptor binding studies. In BIM-43004-1 treated pancreatic cells a 52.5% decrease in intracellular cAMP levels was noted, whereas a 15.3% decrease was seen in PYY treated cells. CONCLUSIONS: BIM-43004-1, a novel Y2 synthetic agonist, specifically binds to human pancreatic cancer cells, decreases intracellular cAMP levels, and suppresses tumor growth in vivo. Adjuvant hormonal treatment with this Y2 receptor analog may be beneficial in the treatment of patients with pancreatic adenocarcinoma.

Animals↗

PubMed1995

Interstitial laser photochemotherapy with new anthrapyrazole drugs for the treatment of xenograft tumors.

Photodynamic therapy (PDT) with lasers and new dyes has gained popularity in recent years as a minimally invasive technique with high tumoricidal effects in vitro and in some cancer patients. However, because new laser dyes are not FDA approved at present, the clinical evaluation of PDT may be years away. During the past 6 years we have used laser alone for photothermal ablation in both preclinical studies and in a large number of patients with an observed 60% tumor response rate. The 40% treatment failure led us to explore the possibility of combined therapy with lasers and standard chemotherapeutic drugs. We have recently tested a promising preclinical alternative using implantation of a bare 600-microns KTP 532 laser fiberoptic in multiple tumor sites 30 min after intratumor injection of the anthrapyrazole DUP-941. As a control, this drug was injected in 3 sites of P3 human squamous cell tumor transplants in nude mice, which led to tumor stasis without regression. Similar 400-600 mm3 tumors exposed to laser illumination alone (0.8 W for 5 sec) at multiple sites resulted in tumor regrowth after 10 weeks in 80% of the animals. However, combining interstitial laser illumination with intratumor DUP-941 injections led to complete tumor regression in 85% of the mice. We propose that intratumor drug injection followed by interstitial laser fiberoptic treatment represents a potentially useful new method for tumor ablation in advanced cancer patients.

Animals↗