To the right, you'll see some new links. I'm now using Google Docs to manage the spreadsheet that holds all Max's lab results. Any time I update the spreadsheet it will update via that link if I'm connected to the I'net. Cool. So all you data freaks have 24/7 access to the latest numbers I have.

Max scans starting tomorrow. His VMA/HVA did a weird flip. VMA shot through the roof to 77! HVA dropped to 39? We are doing another tomorrow to see if this is an anomoly or something terrible is happening.

These are the considerations for what Max will start next week. Based on Max's morphoproteomics report (see link in right column), its likely gemcitibine was doing nothing for him. We won't go back on velcade until his pain from the previous doses diminish or go away. The combo of etoposide/SAHA might work nicely, alternating with vinblastine/rapamycin.

See? Fun!

Cycle 1 – anti-tumor

Journal of Pharmacology And Experimental Therapeutics Fast Forward First published on September 13, 2006; DOI: 10.1124/jpet.106.109397
Proteasome Inhibitors Potentiate Etoposide-Induced Cell Death in Human Astrocytoma Cells Bearing a Mutated p53 Isoform
Stefania Ceruti, Alessia Mazzola, and Maria P. Abbracchio
Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological Sciences, School of Pharmacy, University of Milan, Milan, Italy
Resistance to anticancer agents is often due to defects of intracellular pathways of cell death. Thus, the identification of the apoptotic pathways that can still be recruited by chemotherapeutic agents in cancerous cells can disclose new opportunities to treat malignancies. Here we show that human astrocytoma ADF cells (which are resistant to "mitochondriotropic" agents as well as to the antineoplastic drug etoposide and to proteasome inhibitors when used alone) undergo dramatic apoptotic death when exposed to a combination protocol based on the use of etoposide in the presence of proteasome inhibitors. Sensitization to cell death involved an autoamplifying loop of caspase activation, where the "executioner" phase of apoptosis was sustained by cooperation of caspase-2, -9, -8, and -3. We also show that sensitization of cells to the combination protocol involved the nuclear relocalization of p53, despite the presence of a polymorphism in its DNA-binding domain, suggesting the likely induction of p53-dependent proapoptotic genes. Conversely, p53 phosphorylation on Ser-15 did not play any role in apoptosis. In conclusion, use of etoposide in combination with proteasome inhibitors may represent an effective strategy to restore sensitivity to apoptosis in human astrocytoma cells bearing multiple defects of intracellular apoptotic pathways.

Blood, 15 November 2003, Vol. 102, No. 10, pp. 3765-3774.Prepublished online as a Blood First Edition Paper on August 7, 2003; DOI 10.1182/blood-2003-03-0737.
The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571
Chunrong Yu, Mohamed Rahmani, Daniel Conrad, Mark Subler, Paul Dent, and Steven Grant
From the Departments of Medicine, Radiation Oncology, Biochemistry, Microbiology, Human Genetics, and Pharmacology, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA.

Interactions between the proteasome inhibitor bortezomib and histone deacetylase inhibitors (HDIs) have been examined in Bcr/Abl+ human leukemia cells (K562 and LAMA 84). Coexposure of cells (24-48 hours) to minimally toxic concentrations of bortezomib + either suberoylanilide hydroxamic acid (SAHA) or sodium butyrate (SB) resulted in a striking increase in mitochondrial injury, caspase activation, and apoptosis, reflected by caspases-3 and -8 cleavage and poly(adenosine diphosphate-ribose) polymerase (PARP) degradation. These events were accompanied by down-regulation of the Raf-1/mitogen-induced extracellular kinase (MEK)/extracellular signal-related kinase (ERK) pathway as well as diminished expression of Bcr/Abl and cyclin D1, cleavage of p21CIP1 and phosphorylation of the retinoblastoma protein (pRb), and induction of the stress-related kinases Jun kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Transient transfection of cells with a constitutively active MEK construct significantly protected them from bortezomib/SAHA-mediated lethality. Coadministration of bortezomib and SAHA resulted in increased reactive oxygen species (ROS) generation and diminished nuclear factor B (NF- B) activation; moreover, the free radical scavenger L-N-acetylcyteine (LNAC) blocked bortezomib/SAHA-related ROS generation, induction of JNK and p21CIP1, and apoptosis. Lastly, this regimen potently induced apoptosis in STI571 (imatinib mesylate)-resistant K562 cells and CD34+ mononuclear cells obtained from a patient with STI571-resistant disease, as well as in Bcr/Abl- leukemia cells (eg, HL-60, U937, Jurkat). Together, these findings raise the possibility that combined proteasome/histone deacetylase inhibition may represent a novel strategy in leukemia, including apoptosis-resistant Bcr/Abl+ hematologic malignancies. (Blood. 2003;102:3765-3774)

Cycle 2 – anti-stem-cell/anti-angiogenic

Combined Therapeutic Effects of Vinblastine and Rapamycin on Human Neuroblastoma Growth, Apoptosis, and Angiogenesis
Danilo Marimpietri1, Chiara Brignole1, Beatrice Nico4, Fabio Pastorino1, Annalisa Pezzolo1, Federica Piccardi3, Michele Cilli3, Daniela Di Paolo1, Gabriella Pagnan1, Luca Longo2, Patrizia Perri2, Domenico Ribatti4 and Mirco Ponzoni
Purpose: Vinblastine and rapamycin displayed synergistic inhibition of human neuroblastoma-related angiogenesis. Here, we studied the antitumor activity of vinblastine and rapamycin against human neuroblastoma.
Experimental Design: Cell proliferation, cell cycle progression, and apoptosis were evaluated by measuring 3H-thymidine incorporation, bromodeoxyuridine uptake, and phosphatidylserine exposure, respectively. The in vivo sensitivity of neuroblastoma cells to vinblastine and rapamycin was determined in orthotopic neuroblastoma-engrafted mice. Angiogenesis was assessed by the chick embryo chorioallantoic membrane assay.
Results: Each compound alone was able to induce a dose-dependent significant inhibition of cell proliferation, with a dramatically enhanced antiproliferative effect for the drugs used in combination. A marked G2-M cell cycle arrest with a nearly complete depletion of S phase was associated. The combined treatment triggered an increased apoptosis compared with either drug tested alone. A significant inhibition of tumor growth and microvessel area was obtained in neuroblastoma-bearing mice when treated with vinblastine or rapamycin alone, and a more dramatic effect with the combined treatment, compared with control mice. The therapeutic effectiveness, expressed as increased life span, was statistically improved by the combined therapy, compared with mice treated with either drug tested separately. Histologic evaluation of primary tumors showed that the combined treatment inhibited proliferation and angiogenesis and induced apoptosis. Combined treatment of neuroblastoma cells and neuroblastoma-bearing mice with vinblastine and rapamycin induced the down-modulation of both vascular endothelial growth factor production and vascular endothelial growth factor receptor 2 expression. In the chorioallantoic membrane assay, angiogenesis induced by human neuroblastoma biopsy specimens was significantly inhibited by vinblastine and rapamycin.
Conclusions: These results may be relevant to design new therapeutic strategies against neuroblastoma.


Erin Newman-Smith said...

Dear Andy and Melissa,

We are thinking of you as you sort through all this data with your doctors, trying to find the best treatment plan. This personalized profile of Max's cancer is a great way to go. You two really amaze me in how you do so much for Max, and manage to update your blog, and entertain and care for the rest of your family. You really do live life to the Max!


Anonymous said...

been anxiously awaiting news on scans!!! praying really hard for your little guy!!!!!! Thinking about you guys always!!!!!

ps.. that whole biology study stuff was soo confusing it made my eyes cross!!!! But is exciting business!!!!


rhonda dudley


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