Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Photodynamic therapy (PDT) has been used investigationally for the treatment of lung cancer since 1980. Following systemic administration of a photosensitizing agent such as porfimer sodium (Photofrin; manufactured by Lederle Parenterals, Carolina, Puerto Rico, under license from Quadra Logic Technologies, Inc, Vancouver, British Columbia, Canada), specialized optical delivery systems are engaged to deliver light of a specific wavelength (630 nm for porfimer sodium) to neoplastic tissue. A promising use of PDT appears to be treatment of early stage lung carcinoma. Phase I-II clinical trials by Hayata's group in Japan showed that for superficial early lung cancer less than 1 cm in surface diameter, complete eradication can be achieved in approximately 90% of cases. Additional phase II-III clinical trials have demonstrated an average of 90% complete response rates for superficial tumors less than 1 cm in diameter. Preoperative PDT may be useful for larger neoplasms to reduce tumor burden and potentially lessen the degree of surgery required. At the British Columbia Cancer Agency, 22 patients with 30 radiologically occult cancers were treated with PDT. In contrast to Hayata's studies, most of these patients had rather extensive tumor burden. Thirty percent of the tumors involved two or more bronchi, and more than half of them were greater than 1 cm in surface diameter. Twenty-three percent of the cases were bronchial stump recurrences. In the group of patients with bronchial stump recurrence, although a complete response was obtained with PDT initially, local recurrences occurred in 75% of cases. These results suggest that recurrent tumor in the bronchial stump should not be treated with PDT because of difficulty in delivering light endobronchially to distal tissues. Photodynamic therapy may have a role in the palliation of advanced, inoperable, obstructive bronchial tumors. Phytodynamic therapy in combination with external radiotherapy may produce better local control than external radiotherapy alone in patients with obstructive bronchial cancers. Photodynamic therapy and conventional Nd:YAG laser therapy appear to be equally effective in relieving intraluminal obstruction by tumor. An advantage of PDT for this purpose is longer time to treatment failure; a disadvantage is photosensitization that usually occurs for up to 4 weeks after treatment. In summary, PDT is a promising curative treatment for patients with small early bronchial cancers.
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PMID:Photodynamic therapy of lung cancer. 799 2

Photofrin accumulation in malignant and host cell populations of various tumours was studied by flow cytometry analysis of cells dissociated from the tumour tissue. The transplantable mouse tumour models included in this analysis were sarcomas EMT6, RIF, KHT and FsaN, Lewis lung carcinoma, SCCVII squamous cell carcinoma (SCC) and slowly growing moderately differentiated AT17 SCC. An example of spontaneous mouse adenocarcinoma was also examined. Staining with specific monoclonal antibodies was used to identify the various cell populations present in these tumours. The main characteristic of Photofrin cellular accumulation was a very high photosensitiser content found exclusively in a subpopulation of tumour-associated macrophages (TAMs). Photosensitiser levels similar to or lower than in malignant cells were observed in the remaining TAMs and other tumour-infiltrating host cells. Photofrin accumulation in malignant cells was not equal in all tumour models, but may have been affected by tumour blood perfusion/vascularisation. Results consistent with the above findings were obtained with SCC of buccal mucosa induced by 9,10-dimethyl-1,2-benzanthracene in Syrian hamsters. The TAM subpopulation that accumulates by far the highest cellular Photofrin levels in tumours is suggested to be responsible for the tumour-localised photosensitiser fluorescence.
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PMID:Photofrin accumulation in malignant and host cell populations of various tumours. 859 66

Photofrin is a light-activated compound used for photodynamic therapy (PDT) of malignant tumors. Although PDT with this drug has been approved for clinical use in the United States, Canada, Japan, and the Netherlands there are few published reports on the biodistribution of Photofrin in humans. In this study we report measurable amounts of Photofrin in human serum up to approximately 1 year following injection of two different Photofrin doses. Concentration-time data were collected from 3, 12, 19, and 10 patients after 0.75, 0.875, 1, and 2 mg Photofrin/kg body weight. Patients who received 2 mg Photofrin/kg were scheduled to undergo intraoperative PDT for the treatment of mesothelioma or carcinoma of the lung. Patients receiving 0.75, 0.875, or 1 mg Photofrin/kg were treated for basal cell carcinoma; 1 mg Photofrin/kg is now a standard dose for PDT of cutaneous malignancies at this institute. For the 1 mg Photofrin/kg dose, a triexponential 3-compartment pharmacokinetic model was fitted to 30 data points pooled from the 19 patients, as if we had one "superpatient." The alpha, beta, and gamma halflives were approximately 16 h, 7.53 days, and 155.56 days, respectively. The mean (+/- SEM) serum concentrations 48 after injection (when most tumors are exposed to drug-activating light) of 0.875, 1, or 2 mg Photofrin/kg were 2.70 +/- 0.47, 4.00 +/- 0.66, and 3.47 +/- 0.97 micrograms Photofrin/ml, respectively. No porphyrin fluorescence could be detected in serum collected from patients 560 to 1335 days after Photofrin injection.
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PMID:A preliminary pharmacokinetic study of intravenous Photofrin in patients. 961 97

Photofrin-based photodynamic therapy (PDT) has recently been approved for palliative and curative purposes in cancer patients. It has been demonstrated that neutrophils are indispensable for its anti-tumour effectiveness. We decided to evaluate the extent of the anti-tumour effectiveness of PDT combined with administration of granulocyte colony-stimulating factor (G-CSF) as well as the influence of Photofrin and G-CSF on the myelopoiesis and functional activity of neutrophils in mice. An intensive treatment with G-CSF significantly potentiated anti-tumour effectiveness of Photofrin-based PDT resulting in a reduction of tumour growth and prolongation of the survival time of mice bearing two different tumours: colon-26 and Lewis lung carcinoma. Moreover, 33% of C-26-bearing mice were completely cured of their tumours after combined therapy and developed a specific and long-lasting immunity. The tumours treated with both agents contained more infiltrating neutrophils and apoptotic cells then tumours treated with either G-CSF or PDT only. Importantly, simultaneous administration of Photofrin and G-CSF stimulated bone marrow and spleen myelopoiesis that resulted in an increased number of neutrophils demonstrating functional characteristics of activation. Potentiated anti-tumour effects of Photofrin-based PDT combined with G-CSF observed in two murine tumour models suggest that clinical trials using this tumour therapy protocol would be worth pursuing.
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PMID:Potentiation of the anti-tumour effects of Photofrin-based photodynamic therapy by localized treatment with G-CSF. 1078 May 31

Photodynamic therapy is an effective and often curative treatment for certain solid tumors. The porphyrin-based photosensitizer Photofrin, the only Food and Drug Administration-approved drug for this therapy, suffers from certain disadvantages: its complex chemical nature; retention by skin (leading to protracted cutaneous photosensitivity); and less than optimal photophysical properties. In this study, we examine the population pharmacokinetics and cutaneous phototoxicity of 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), a chlorin-type photosensitizer with more favorable photophysical properties. HPPH plasma concentration-time data were obtained in 25 patients enrolled in Phase I-II clinical trials for the treatment of partially obstructive esophageal carcinoma, high-grade dysplasia associated with Barrett's esophagus, carcinoma of the lung, or multiple basal cell carcinomas. Doses of 3, 4, 5, or 6 mg/m(2) were administered as 1-h i.v. infusions. The pharmacokinetic data for each patient were fitted with a standard two-compartment (biexponential) model with continuous infusion. The model fitting approach was iteratively reweighted nonlinear regression, with weights equal to the reciprocal of the square of the predicted HPPH plasma concentrations. The complete set of data for all 25 patients was then fitted simultaneously with nonlinear mixed effects modeling. Cutaneous phototoxicity responses were determined, as a function of time after HPPH infusion, following exposure to various doses of light from a solar simulator. The estimates of the population mean (variance) for each parameter were as follows: volume of distribution (V(C)), 2.40 liters/m(2) (0.259); steady-state volume (V(SS)), 9.58 liters/m(2) (11.6); systemic clearance (CL), 0.0296 liter/h/m(2) (0.000094); and distributional clearance (CL(D)), 0.144 liter/h/m(2) (0.00166). These parameters were independent of dose. Clearance increased with age. A relative error model was used for the difference in the raw and fitted data, and the overall coefficient of variation estimate across all of the data was 14.5%. The estimated mean population alpha and beta half-lives (95% confidence interval) were 7.77 h (3.46-17.6 h) and 596 h (120-2951 h), respectively. High-performance liquid chromatography analysis of serum showed no circulating HPPH metabolites, and in vitro incubation of HPPH with human liver microsomal preparations resulted in no metabolite or glucuronic acid-HPPH conjugate production. A minimal skin response to the solar simulator was observed, mostly in patients treated with the highest dose of HPPH, 6 mg/m(2). All of the HPPH pharmacokinetic parameters were consistent with a highly lipophilic agent that is concentrated in plasma and is nearly 100% bound to plasma proteins; this was verified by plasma protein binding studies. Whereas low concentrations of HPPH can be detected in plasma several months after a single infusion, no instances of cutaneous photosensitivity have been noted in these patients. In general, HPPH pharmacokinetic profiles are readily predictable from the global population model. This is the first comprehensive human population pharmacokinetic/pharmacodynamic study of a clinical anticancer photodynamic therapy agent.
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PMID:Population pharmacokinetics of the photodynamic therapy agent 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a in cancer patients. 1270 66

Photofrin is the most commonly used photosensitizer for photodynamic therapy (PDT). The major side effect of Photofrin is cutaneous photosensitivity. A second generation photosensitizer, mono-L-aspartyl chlorin e6 (NPe6) has shown anti-tumor efficacy and rapid clearance from skin. Therefore, we conducted a phase II clinical study to investigate the anti-tumor effects and safety of NPe6 in patients with early superficial squamous cell carcinoma of the lung. Enrollment criteria consisted of endoscopically evaluated early stage lung cancer with normal chest X-ray and CT images, no lymph node or distant metastasis. Tumors were located no more peripherally than subsegmental bronchi, the peripheral margin had to visible, and the tumor size had to not more than 2 cm in diameter. The histologic type of the tumor had to squamous cell carcinoma. Laser irradiation (100 J/cm2) using a diode laser was performed at 4 h after administration of NPe6 (40 mg/m2). Among 41 patients with 46 lesions, 40 with 45 lesions were eligible for safety evaluation, and 35 patients with 39 lesions were judged as eligible for efficacy evaluation. No serious adverse drug reactions were observed. Disappearance of skin photosensitivity was recognized within 2 weeks in 28 of 33 patients (84.8%) and in all the other seven patients first tested at 15-18 days. Complete response (CR) was seen in 84.6% of lesions (82.9% of patients). This study demonstrated excellent anti-tumor effects and safety, especially low skin photosensitivity in patients with early stage lung cancer. PDT using the second generation photosensitizer NPe6 and a diode laser will likely become a standard modality of PDT for central type early superficial squamous cell carcinoma of the lung.
Lung Cancer 2003 Oct
PMID:Phase II clinical study of photodynamic therapy using mono-L-aspartyl chlorin e6 and diode laser for early superficial squamous cell carcinoma of the lung. 1451 94

Patients with advanced non-small-cell lung carcinoma (NSCLC) have poor prognoses and experience negative sequelae of disease. Patients often suffer from dyspnea and/or hemoptysis, with overall pulmonary compromise. Patients with advanced, inoperable disease have limited options for treatment. This study summarizes our early experience and findings using photodynamic therapy (PDT) as an effective modality in the palliation of hemoptysis, dyspnea, and physical airway obstruction in cases of inoperable lung cancer. A retrospective review was conducted for the first 10 patients diagnosed with stage III/IV obstructive NSCLC who underwent PDT at our institution. Endobronchial lesions were identified by bronchoscopy. Treatments were initiated 48 hours after intravenous injection of 2 mg/kg of the photosensitizing agent porfimer sodium (Photofrin, QLT PhotoTherapeutics, Vancouver, BC). The porfimer sodium was then activated by illumination with a 630 nm wavelength light using a Coherent argon ion laser through a flexible bronchoscope. Repeated bronchoscopies were performed 1-3 days following initial PDT for evaluation and airway debridement. In 8 cases, a second treatment of PDT was administered within 72 hours of the first injection. One patient received a third treatment several months later. Three patients also received endobronchial stents after PDT. Overall, all 10 patients responded to PDT. Physical airway obstruction was reduced in all patients, with a noted improvement in bronchoscopic luminal diameter. Acute hemoptysis resolved in all 7 symptomatic patients. Median survival was 5.5 months post-PDT, while median survival postdiagnosis was 10.5 months. Three patients are alive at the time of this review at 5-21 months following therapy. Patients with unresectable late-stage NSCLC have few options for treatment. Our early experience with PDT indicates effective relief of hemoptysis, dyspnea, and airway obstruction and improves their quality of life.
Clin Lung Cancer 2001 Aug
PMID:Photodynamic therapy for patients with advanced non-small-cell carcinoma of the lung. 1465 88

Photodynamic therapy (PDT) has now achieved the status of a standard treatment modality for centrally located early-stage lung cancer. In the last decade, CT screening for lung cancer has attracted much attention for its ability to detect early peripheral lung cancer. Extremely recently, treatment using PDT has been introduced for the first time in patients with peripheral lung cancer, who did not meet the previous criteria for surgery. The procedure was carried out with local anesthesia with xylocain infiltrated into the chest wall, 48 h after Photofrin administration. Needles (19 gauge) containing an internal catheter were inserted percutaneously under CT guidance. The needles were then extracted and a diffuser fiber with a 2 cm long tip for light delivery was positioned in the tumor through the catheter. Of the nine patients enrolled in this trial, seven achieved partial remission (PR). No serious complications, except for two cases of pneumothorax, were noted. As an increasing number of patients consider quality of life after therapy, the indications for PDT are expected to expand. We conclude that PDT is a promising new technique for curative treatment of localized, peripheral lung cancer less than 1cm in size in patients who are unfit for surgery or radiotherapy.
Lung Cancer 2004 Jan
PMID:Photodynamic therapy for peripheral lung cancer. 1469 41

Cancer therapies, which deliver a rapidly induced massive tumor tissue injury, such as photodynamic therapy (PDT), provoke a strong host response raised for dealing with the inflicted local trauma. Activated complement system was identified as an important element of host response elicited by tumor PDT. The expression of genes encoding complement proteins C3, C5, and C9 was studied following tumor PDT mediated by photosensitizer Photofrin using mouse Lewis lung carcinoma (LLC) model. Treated tumors and the livers of host mice were collected at different times after PDT and the expression of the investigated genes was analyzed by RT-PCR. The results show a significant up-regulation of C3, C5, and C9 genes in PDT-treated tumors at 24 h after therapy, while no significant increase in the expression of these genes was found in the liver tissues. The expression of C3, C5, and C9 genes also became up-regulated in untreated tumor-associated macrophages (TAMs) co-incubated in vitro with PDT-treated LLC cells. This effect was abolished or drastically reduced in the presence of antibodies blocking heat shock protein 70 (HSP70), Toll-like receptor (TLR) 2 and TLR4, and specific peptide inhibitors of TIRAP adapter protein and transcription factor NF-kappaB. The presented study reveals that complement genes C3, C5, and C9 become up-regulated in tumors treated by PDT, but not in the host's liver. Tumor-localized up-regulation of these genes can be largely attributed to monocytes/macrophages invading the treated lesion after PDT. This effect appears to be induced by the recognition of danger signals from PDT-treated tumor cells such as HSP70 by TAMs that involve the TLR2- and TLR4-triggered signal transduction pathways leading to the activation of NF-kappaB.
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PMID:Activation of complement C3, C5, and C9 genes in tumors treated by photodynamic therapy. 1694 20

Serum amyloid P component (SAP) is known as a prototypic acute phase reactant in the mouse and the protein that binds to dying cells securing their swift disposal by phagocytes. Treatment of solid tumors by photodynamic therapy (PDT) triggers SAP production in the liver of host mice, its release in the circulation and accumulation in PDT-targeted lesions. In the present study, mouse Lewis lung carcinoma (LLC) cells treated in vitro by PDT are shown to upregulate their gene encoding SAP. This effect was manifested following PDT treatment mediated by various types of photosensitizers (Photofrin, BPD, mTHPC, ALA). Generated SAP protein was not detected in tissue supernatants but remained localized to producing PDT-treated cells. The upregulation of SAP gene was observed also in untreated IC-21 macrophages after they were co-incubated for 4 h with PDT-treated LLC cells. Based on these findings, SAP that accumulates in PDT-treated tumors may originate from both systemic sources (released from the liver as acute phase reactant) and local sources; the latter could include tumor cells directly sustaining PDT injury and macrophages invading the tumor that become stimulated by signals from these affected tumor cells. Since SAP gene upregulation in LLC cells increased with the lethality of PDT dose used for their treatment, we propose that cells sensing they are inflicted with mortal injury can turn on molecular programs insuring not only that they die an innocuous form of death (apoptosis) but also that once they are dead their elimination is (facilitated by SAP) swift and efficient.
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PMID:Dying cells program their expedient disposal: serum amyloid P component upregulation in vivo and in vitro induced by photodynamic therapy of cancer. 1804 83


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