Chlorin E6-Curcumin-Mediated Photodynamic Therapy Promotes an Anti-Photoaging Effect in UVB-Irradiated Fibroblasts.

Skin photoaging due to ultraviolet B (UVB) exposure generates reactive oxygen species (ROS) that increase matrix metalloproteinase (MMP). Chlorin e6-photodynamic therapy (Ce6-PDT), in addition to being the first-line treatment for malignancies, has been shown to lessen skin photoaging, while curcumin is well known for reducing the deleterious effects of ROS. In the current study, PDT with three novel Ce6-curcumin derivatives, a combination of Ce6 and curcumin with various linkers, including propane-1,3-diamine for Ce6-propane-curcumin; hexane-1,6-diamine for Ce6-hexane-curcumin; and 3,3'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(propan-1-amine) for Ce6-dipolyethylene glycol (diPEG)-curcumin, were studied for regulation of UVB-induced photoaging on human skin fibroblast (Hs68) and mouse embryonic fibroblast (BALB/c 3T3) cells. We assessed the antiphotoaging effects of Ce6-curcumin derivatives on cell viability, antioxidant activity, the mechanism of matrix metalloproteinase-1 and 2 (MMP-2) expression, and collagen synthesis in UVB-irradiated in vitro models. All three Ce6-curcumin derivatives were found to be non-phototoxic in the neutral red uptake phototoxicity test. We found that Ce6-hexane-curcumin-PDT and Ce6-propane-curcumin-associated PDT exhibited less cytotoxicity in Hs68 and BALB/c 3T3 fibroblast cell lines compared to Ce6-diPEG-curcumin-PDT. Ce6-diPEG-curcumin and Ce6-propane-curcumin-associated PDT showed superior antioxidant activity in Hs68 cell lines. Further, in UVB-irradiated in vitro models, the Ce6-diPEG-curcumin-PDT greatly attenuated the expression levels of MMP-1 and MMP-2 by blocking mitogen-activated protein kinases (MAPKs), activator protein 1 (AP-1), and tumor necrosis factor-α (NF-κB) signaling. Moreover, Ce6-diPEG-curcumin effectively inhibited inflammatory molecules, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, while accelerating collagen synthesis. These results demonstrate that Ce6-diPEG-curcumin may be a potential therapy for treating skin photoaging.

Long-term outcomes of concomitant chemoradiotherapy incorporating high-dose-rate brachytherapy to treat locally advanced cervical cancer.

AIM AND BACKGROUND: We reviewed the long-term clinical outcomes of patients treated with cisplatin-based concurrent chemoradiotherapy (CCRT) incorporating high-dose-rate (HDR) intracavitary brachytherapy (ICBT) in terms of toxicity, local control and survival rates. In addition, we identified prognostic factors for overall and disease-free survival. METHODS AND STUDY DESIGN: . Two hundred and nine patients with stage IB2-IVA cervical cancer underwent curative cisplatin-based CCRT plus HDR ICBT. Women with stage IB2-IIB disease were given 41.4 Gy of external radiotherapy followed by 35 Gy (in 7 fractions) of ICBT. Women with stage IIIA-IVA were given 50.4 Gy followed by 30 Gy (in 6 fractions) of ICBT. Patients with parametrial disease or pelvic lymphadenopathy were given parametrial boosts via external beam radiation at a dose of up to 65 Gy to thickened and 60 Gy to unthickened parametrial regions. RESULTS: One hundred and thirty (62%) patients experienced acute grade 3-4 hematological toxicities and 11 (5%) patients had late grade 3 gastrointestinal or genitourinary complications. Complete responses occurred in 168 (80%) women as determined by clinical and imaging studies. The median follow-up period was 52 months for surviving patients and the 5-year overall and disease-free survival rates were 74% and 67%, respectively. Multivariate analysis indicated that tumor size and paraaortic lymph node involvement were prognostically significant in terms of overall survival, and that tumor diameter was a significant prognostic factor and pelvic lymph node status a marginally significant prognostic factor for disease-free survival. CONCLUSIONS: Patients treated with our current HDR ICBT protocol have acceptably low late complication rates and local control and survival rates comparable to those reported in other studies. Tumor diameter was an important prognostic factor in terms of both overall and disease-free survival, emphasizing the need for modern ICBT methodologies.

Radiation therapy is a treatment to be considered for recurrent epithelial ovarian cancer after chemotherapy.

AIMS AND BACKGROUND: Radiation therapy provides a safe and effective alternative treatment option for recurrent epithelial ovarian cancer, although it has not been a treatment of choice. We evaluated the efficacy and toxicity of radiation therapy for recurrent epithelial ovarian cancer after chemotherapy according to the disease status. METHODS: This was a retrospective study of 38 patients with recurrent epithelial ovarian cancer treated with radiation therapy at the Asan Medical Center, Seoul, Korea, between January 1997 and December 2007. We analyzed their clinical characteristics and the outcome of radiation therapy. RESULTS: Thirty-eight patients were treated with radiation therapy. Their median age was 51.5 years. Most patients were FIGO stage III (27/38) with serous adenocarcinoma (26/38). All patients had received at least one regimen of platinum-based chemotherapy; 24 patients were sensitive to the first chemotherapy and the others were resistant. Lymph node and abdominopelvic wall were the most common sites of radiation therapy. The response rate was 65.0% (16 complete remissions and 10 partial remissions), and the median regression rate was 78.8% (range, -66.6 to 100.0). Median progression-free survival was 7.2 months (range, 1.0-66.6). In 28 patients who had a solitary relapsed site from the radiographic finding at the time of radiation therapy, it was 10.7 months (range, 1.8-66.6). Neither hematologic nor intestinal toxicity of grade 3-4 was observed. Prognostic factors were sensitivity to platinum and the site treated with radiation therapy. CONCLUSIONS: Radiation therapy is a treatment that should be considered for recurrent epithelial ovarian cancer, especially in good responders to platinum or patients with solitary relapsed lesions.

Concurrent chemoradiotherapy or radiotherapy alone for locally advanced cervical cancer in elderly women.

AIMS AND BACKGROUND: To evaluate the efficacy and toxicity of concurrent chemoradiotherapy or radiotherapy alone in elderly patients with locally advanced cervical carcinoma (stage IB2-IVA). METHODS AND STUDY DESIGN: We retrospectively reviewed the medical records of 105 women aged 265 years who received radiotherapy (group I, n=61) or concurrent chemoradiotherapy (group II, n=44). Patients received a median dose of 76.4 Gy to point A, including 30-35 Gy of high-dose intracavity brachytherapy. The concurrent chemoradiotherapy group received platinum-based chemotherapy. RESULTS: The median follow-up was 65 months for surviving patients. There was no significant difference in compliance to radiotherapy between the two groups. Most acute toxicities were hematologic; acute hematologic and gastrointestinal toxicity were significantly more common in group II. Five-year overall survival and cancer-specific survival rates were, respectively, 53.5% and 66.6% in group I and 61.8% and 68.8% in group II. Performance status, comorbidity index, tumor size, and stage were independent prognostic factors for overall survival, whereas stage was the only prognostic factor for cancer-specific survival. CONCLUSIONS: The analysis showed no benefit of concurrent chemoradiotherapy with respect to overall survival and cancer-specific survival in elderly women. A prospective study is needed to determine the role of concurrent chemoradiotherapy in this population.

Water-soluble porphyrin-polyethylene glycol conjugates with enhanced cellular uptake for photodynamic therapy.

Water soluble porphyrins were designed and prepared by Williamson ether synthesis reaction between tetrakis(p-bromomethylphenyl)porphyrin and polyethylene glycol (PEG) for photodynamic therapy. The quantum yields for the generation of singlet oxygen of tetra-polyethylene glycol branched porphyrin shows above 80% in D2O. Luminescence of singlet state oxygen was observed from D2O solution under the single-photon excitation at 514 nm. In vitro test, cellular uptake efficiency has been enhanced by simple modification of molecular structure through changing the number of PEG unit without any support such as polymer-encapsulated inorganic nanoparticles.

High-dose extended-field irradiation and high-dose-rate brachytherapy with concurrent chemotherapy for cervical cancer with positive para-aortic lymph nodes.

PURPOSE: To determine the efficacy and toxicity of extended-field radiotherapy (RT) with concurrent platinum-based chemotherapy in patients with uterine cervical carcinoma and positive para-aortic nodes. METHODS AND MATERIALS: We retrospectively reviewed the results for 33 women with Stage IB-IVB cervical cancer. Each patient had received 59.4 Gy, including a three-dimensional conformal boost to the para-aortic lymph nodes and 41.4-50.4 Gy of external beam radiotherapy to the pelvis. Each patient also underwent six or seven applications of high-dose-rate brachytherapy (median, 5 Gy to point A at each session). RESULTS: The median follow-up period of surviving patients was 39 months. The most common acute toxicity was hematologic, observed in 23 women. Severe acute and late gastrointestinal toxicity was observed in 3 and 4 patients, respectively. More than three-quarters of patients showed a complete response, encompassing the primary mass, metastatic pelvic, and para-aortic lymph nodes. Of the 33 women, 15 had no evidence of disease, 6 had persistent disease, 4 developed in-field failures, and 6 developed distant failures. The 5-year overall and disease-free survival rate was 47% and 42%, respectively. CONCLUSION: Concurrent chemoradiotherapy with extended-field radiotherapy is feasible in women with uterine cervical carcinoma and positive para-aortic lymph nodes, with acceptable late morbidity and a high survival rate, although it was accompanied by substantial acute toxicity.

Prospective randomized comparison of monthly fluorouracil and cisplatin versus weekly cisplatin concurrent with pelvic radiotherapy and high-dose rate brachytherapy for locally advanced cervical cancer.

OBJECTIVE: To compare monthly fluorouracil (FU) plus cisplatin and weekly cisplatin concurrent with radiotherapy for locally advanced cervical cancer. METHODS: A total of 158 patients (stages IIB through IVA) without para-aortic lymph nodes were randomized to receive 3 monthly cycles of FU (1000 mg/m2/day i.v.) plus cisplatin (20 mg/m2/day i.v.) for 5 days (group I, n=79) or 6 cycles of weekly cisplatin (30 mg/m2 i.v.) (group II, n=79), concurrent with definitive radiotherapy. Radiotherapy consisted of external irradiation to the whole pelvis of 41.4-50.4 Gy in 23-28 fractions plus high-dose rate (HDR) intracavitary brachytherapy (30-35 Gy in 6-7 fractions) to point A, together with a parametrial boost. Compliance with treatment, toxicity, response, and survival was analyzed and compared. RESULTS: Of the 158 women, 155 women were eligible for analysis; the median follow-up of surviving patients was 39 months. Full planned chemoradiotherapy was delivered to 47 (60%) and 55 (71%) patients in groups I and II, respectively. The incidence of acute grade 3/4 hematologic toxicity was 43% and 26% (p=0.037). The complete response rate of each group was 91%. Four-year overall and progression-free survival rates were 70% and 67%, respectively, in group I and 67% and 66%, respectively, in group II. CONCLUSIONS: The regimen of chemoradiation using weekly cisplatin significantly improves compliance with treatment and reduces acute hematologic toxicity, while not affecting response and survival rates.