motexafin-gadolinium and Carcinoma--Squamous-Cell

Motexafin gadolinium (MGd) disrupts redox-dependent pathways by inhibiting oxidative stress-related proteins leading to apoptosis. MGd selectively targets tumor cells, disrupting energy metabolism and repair mechanisms, rendering cells more prone to apoptosis. Preclinical studies with MGd and pemetrexed show significant tumor growth delay in lung cancer cell lines.. Patients with non-small cell lung cancer, Eastern Cooperative Oncology Group performance status 0 to 1, who had received one previous platinum containing regimen and normal organ function were treated with MGd 15 mg/kg and pemetrexed 500 mg/m q21days. Patients were allowed to receive more than one regimen if the initial treatment was in the adjuvant or curative setting and administered >12 months earlier. The primary end point was to demonstrate a 40% rate of 6-month progression free survival (PFS).. Seventy-two patients (30 women, 42 men), performance status 0/1 (30/42), and a median age of 63 years were enrolled. Most patients (96%) were current or former smokers. All histologic types were represented (squamous/adenocarcinoma/other: 28%, 42%, 31%). Number of prior regimens: 1: 69%; 2: 26%, and >2: 4%. Median number of cycles administered was (range) 2 (1-12).. grade 3/4 neutropenia was noted in 8.3% with febrile neutropenia in 1.4%, thrombocytopenia in 8.3%, fatigue in 9.7%, and pneumonia in 11.1%. There were no complete responses, 8.1% had partial response, 56.5% had stable disease, and 35.5% had progressive disease as their best response. Twenty-three percent of patients were progression free at 6 months and the median PFS was 2.6 months with an overall survival of 8.1 months.. The combination of MGd and pemetrexed was well tolerated with toxicity similar to that of pemetrexed alone. However, the study did not achieve its end point of 40% 6-month PFS. The response rate, PFS, and overall survival did not seem markedly different than prior phase II and phase III studies of pemetrexed alone. Consequently, there are no further plans for development of this combination.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Female; Follow-Up Studies; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Metalloporphyrins; Middle Aged; Neoplasm Staging; Pemetrexed; Pilot Projects; Prognosis; Salvage Therapy; Survival Rate

Motexafin gadolinium is a novel antineoplastic drug that disrupts cancer cell antioxidant systems, thus contributing to cellular death. In patients with lung cancer, motexafin gadolinium has been shown to increase the time to neurologic progression when given in combination with whole-brain radiotherapy in randomized phase III studies. Preclinical data suggest that this drug might also enhance the antineoplastic effects of chemotherapy.. In this one-arm, open label, phase I, dose-escalation study, we administered docetaxel (75 mg/m2), cisplatin (75 mg/m2), and motexafin gadolinium every 3 weeks to patients with metastatic non-small cell lung cancer. Twenty-one patients were treated at one of four motexafin dose levels.. The maximal tolerated motexafin dose was 10 mg/kg on day 1 of a 3-week cycle. Dose-limiting toxicities consisted of febrile neutropenia, hypertension, myocardial ischemia, and pneumonitis/pulmonary infiltrates. Other common grade 3-4 adverse events across all cohorts that did not appear to be exacerbated by motexafin gadolinium included granulocytopenia, fatigue, dehydration, nausea, and vomiting. Two episodes of myocardial ischemia and one sudden death of unknown cause were observed. Response rates were partial response (10%), stable disease (60%), and disease progression (30%).. The regimen studied was tolerable and showed activity in patients with metastatic non-small cell lung cancer. The recommended doses for future phase II trials are motexafin gadolinium 10 mg/kg, docetaxel 75 mg/m2, and cisplatin 75 mg/m2 intravenously on day 1 every 3 weeks. Caution is advised in patients with a history of cardiovascular disease.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cisplatin; Docetaxel; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Metalloporphyrins; Middle Aged; Prognosis; Survival Rate; Taxoids

We have investigated the pharmacokinetics (PK) of Lutetium Texaphyrin (Lu-Tex), a second-generation photosensitizer, in the Syrian hamster cheek pouch early cancer model. Ten male hamsters, five with chemically induced early squamous cell cancer of the left cheek pouch, received an intracardiac injection of a 10 mg/ml Lu-Tex solution, resulting in a dose of 12 mg Lu-Tex per kg of bodyweight. The PK of the dye have been measured during the 24 h following the injection with an optical-fiber-based spectrofluorometer on the ventral skin, the healthy and the tumoral cheek-pouch mucosa. The Lu-Tex fluorescence is excited at 460 nm and detected around 740 nm. All the measurements yield very similar pharmacokinetic curves. The fluorescence intensity reaches a maximum between two and three hours after the injection and, at its maximum, it is consistently higher (up to 1.5 times) on the tumor than on the healthy mucosa. It remains smaller on the skin than on cheek-pouch mucosa. After 24 h, the Lu-Tex fluorescence is no longer detectable either on the skin, on the lesion or on the healthy mucosa. Moreover, Lu-Tex clearly displays a significant fluorescence selectivity between early carcinoma and healthy mucosa in this model. Furthermore, the inter-animal fluctuations of the fluorescence signal are small (+/-16% on the tumor-bearing mucosa). Eight-minute-long skin-irradiation tests have been performed 24 h after the injection of the Lu-Tex on the ventral skin of 16 additional animals with a solar simulator. No reaction is observed, either macroscopically or microscopically, which further demonstrates, as suggested by the fluorescence measurements, that this photosensitizer is significantly cleared from the skin after 24 h.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma in Situ; Carcinoma, Squamous Cell; Cricetinae; Male; Mesocricetus; Metalloporphyrins; Microscopy, Fluorescence; Mouth Mucosa; Mouth Neoplasms; Photosensitizing Agents; Skin; Sunlight

The aim of this study is to modify the chick chorioallantoic membrane (CAM) model into a whole-animal tumor model for photodynamic therapy (PDT). By using intraperitoneal (i.p.) photosensitizer injection of the chick embryo, use of the CAM for PDT has been extended to include systemic delivery as well as topical application of photosensitizers. The model has been tested for its capability to mimic an animal tumor model and to serve for PDT studies by measuring drug fluorescence and PDT-induced effects. Three second-generation photosensitizers have been tested for their ability to produce photodynamic response in the chick embryo/CAM system when delivered by i.p. injection: 5-aminolevulinic acid (ALA), benzoporphyrin derivative monoacid ring A (BPD-MA), and Lutetium-texaphyrin (Lu-Tex). Exposure of the CAM vasculature to the appropriate laser light results in light-dose-dependent vascular damage with all three compounds. Localization of ALA following i.p. injections in embryos, whose CAMs have been implanted with rat ovarian cancer cells to produce nodules, is determined in real time by fluorescence of the photoactive metabolite protoporphyrin IX (PpIX). Dose-dependent fluorescence in the normal CAM vasculature and the tumor implants confirms the uptake of ALA from the peritoneum, systemic circulation of the drug, and its conversion to PpIX.

Topics: Allantois; Aminolevulinic Acid; Animals; Biological Transport; Carcinoma, Squamous Cell; Cell Division; Chick Embryo; Chorion; Female; Kinetics; Metalloporphyrins; Ovarian Neoplasms; Photosensitizing Agents; Porphyrins; Rats; Rats, Inbred F344; Tumor Cells, Cultured