Harold and CI,
I don't know if PCYC is a good investment right now, but it certainly is an interesting one. We should get Phase III results this year, and if they are favorable the stock should move very dramatically higher. Remember they own this drug 100% and potentially it could be used in nearly all radiation therapy. (There are 700,000 patients treated annually with radiation). There is also considerable potential from their "roto-rooter" treatment.
That's the upside. On the downside:
1. The company has been very reticent about discussing setbacks - little news on the Lutrin breast cancer trial, and how long did it take them to admit that their imaging agent was dead?
2. The unresolved issue of the conflicting preclinical data set out in the paper by Brown et al. This is pretty murky, particularly given that there now seems to have been some independent validation of the PCYC work (see abstract below). At one point there was talk of the NCI doing some tests. Anyone heard anything about it? In any event, this issue will be trumped by the clinical results from the Phase III trial.
Here's the abstract:
Int J Radiat Oncol Biol Phys 2001 Apr 1;49(5):1381-90 Related Articles, Books, LinkOut
Effects of Motexafin gadolinium on tumor metabolism and radiation sensitivity.
Xu S, Zakian K, Thaler H, Matei C, Alfieri A, Chen Y, Koutcher JA.
Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
PURPOSE: Experiments were undertaken to determine if metabolic changes induced by Motexafin gadolinium (Gd-Tex(+2), XCYTRIN) predict time intervals between drug and radiation wherein there is enhancement of radiation efficacy. METHODS AND MATERIALS: We evaluated the effect of Gd-Tex(+2) on tumor metabolism and on tumor growth using a mouse mammary carcinoma model and (31)P nuclear magnetic resonance (NMR) experiments. Response to therapy was evaluated based on time for the tumor to regrow to pretreatment size and also tumor doubling time. RESULTS: (31)P NMR experiments indicated that Gd-Tex(+2) effected tumor energy metabolism during the first 24 hours postadministration. A decrease in phosphocreatine was noted at 2 (p < 0.04), 6 (p < 0.006), and 24 (p < 0.001) hours post Gd-Tex(+2). A decrease in nucleoside triphosphates was noted only at 2 hours (p < 0.02), with subsequent recovery at 6 hours. Phosphocreatine in control (saline treated) tumors showed a significant decrease only at 24 hours (p < 0.01). Irradiation at 2 and 6 hours post Gd-Tex(+2) induced an enhanced effect compared to radiation alone as measured by analyzing the growth curves, maximum tumor volumes, and the time for the tumors to regrow to their initial volumes. Irradiation at 24 hours post Gd-Tex(+2) induced a modest enhancement in tumor growth delay compared to radiation alone. DISCUSSION: NMR spectroscopy may be useful for monitoring tumor metabolism after treatment with Gd-Tex(+2) and administering radiation during the time of maximal efficacy of Gd-Tex(+2).
And here are two roto-rooter abstracts:
Transplantation 2001 Jun 15;71(11):1526-32 Related Articles, Books, LinkOut
Photodynamic therapy with motexafin lutetium (Lu-Tex) reduces experimental graft coronary artery disease.
Yamaguchi A, Woodburn KW, Hayase M, Hoyt G, Robbins RC.
Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, CA 94305, USA. robbins@leland.stanford.edu
BACKGROUND: Motexafin lutetium (Lu-Tex) is a photodynamic therapy (PDT) agent that localizes in atheromatous plaque in which it can be activated by far-red light. Lu-Tex biolocalization was examined in graft coronary artery disease (GCAD) with a rodent allograft model. After photoactivation, the effect on intimal proliferation was assessed. METHODS: A PVG to ACI rat heterotopic heart transplantation model was used. Lu-Tex (10 mg/kg) was intravenously administered 90 days after transplantation. Photoactivation was performed 24 hr after Lu-Tex administration. A light-emitting diode, central wavelength of 742 nm, was used to illuminate the intraperitoneally placed allografts via a laparotomy (light fluence of 75 J/cm2 at a power density of 75 mW/cm2). Animals were divided into four groups according to postoperative treatments: PDT with Lu-Tex injection and light illumination (n=21), Lu-Tex injection and laparotomy (n=14), laparotomy with light only (n=14), and laparotomy only (n=16). GCAD was quantitatively assessed 14 days after treatments. RESULTS: Lu-Tex localized in atherosclerotic plaque in vessels with GCAD. PDT significantly reduced both the percent of affected vessels and intimal proliferation compared to all other control study groups. alpha-Smooth muscle cell actin and anti-rat macrophage antibody-positive areas were significantly reduced within the neointima in allografts treated with PDT compared to all other study groups. CONCLUSIONS: PDT significantly reduced atherosclerotic lesions of GCAD. Lu-Tex-mediated PDT may, therefore, be a potential method for treating accelerated atherosclerosis associated with transplantation.
Arterioscler Thromb Vasc Biol 2001 May;21(5):759-64 Related Articles, Books, LinkOut
Photodynamic therapy with motexafin lutetium induces redox-sensitive apoptosis of vascular cells.
Chen Z, Woodburn KW, Shi C, Adelman DC, Rogers C, Simon DI.
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Motexafin lutetium is a photosensitizer that accumulates in atherosclerotic plaque and, after activation by far-red light, produces cytotoxic singlet oxygen. The combination of photosensitizer and illumination, known as photodynamic therapy (PDT), has been shown to reduce atheroma formation in animal models and is under clinical investigation. However, the effects of PDT with motexafin lutetium on isolated vascular cells are unknown. This study was designed to characterize the effects of PDT on vascular cell viability and to define the cell-death pathway for this agent. Fluorescence microscopy of RAW macrophages and human vascular smooth muscle cells revealed time-dependent uptake of motexafin lutetium. Illumination of motexafin lutetium-loaded cells with 732-nm light (2 J/cm(2)) impaired cellular viability and growth (IC(50) 5 to 20 micromol/L). Depletion of intracellular glutathione potentiated (P=0.035) and the addition of antioxidant N-acetylcysteine attenuated (P=0.002) cell death, suggesting that the intracellular redox state influences motexafin lutetium action. PDT was associated with the loss of mitochondrial membrane potential, mitochondrial release of cytochrome c, and caspase activation. PDT promoted phosphatidylserine externalization and induced apoptotic DNA fragmentation, with the number of apoptotic cells increasing from 7+/-2% to 34+/-3% of total cells. Reducing plaque cellularity by the induction of apoptosis may be one mechanism by which PDT reduces plaque burden, possibly modulates plaque vulnerability, and inhibits restenosis in vivo.
Peter |
