RFC Study p53 Transmittal C

[Guest guest]

Now putting these abstracts aside, you may find of interest a study

published in Blood, 15 January 2005, Vol. 105, No. 2, pp. 767-774,

titled " Quantitative analysis of nucleoside transporter and

metabolism gene expression in chronic lymphocytic leukemia (CLL):

identification of fludarabine-sensitive and -insensitive populations "

(http://bloodjournal.hematologylibrary.org/cgi/content/full/105/2/767)

This paper explicitly states: " Resistance to fludarabine is observed

in the clinic, and molecular predictive assays for benefit from

chemotherapy are required. " Within their conclusions, they

note: " Subjects with elevated hCNT3 expression experienced a lower

complete response rate to fludarabine therapy (11% vs 69%; P = .002).

No hCNT3-mediated plasma membrane nucleoside transport was detected

in CLL samples expressing hCNT3 message, and hCNT3 protein was

localized to the cytoplasm with immunohistochemical and confocal

microscopy. "

In scanning through my notes, in addition to provided info, I came

across an ACOR CLL posting of your's to Dr. Hamblin, back in August

of this year, noting you had the p53 deletion but were mutated, ZAP-

70 & CD38 negative. Dr. Hamblin replied, in part, " if you need

treatment it is likely that you will not respond to fludarabine. The

options are Campath, high dose steroids and revlimid. You might

respond to the new HuMax CD20 antibody from early reports. "

Subsequently, in response to further clarification requested by Karni

, Dr. Hamblin noted: " Fludarabine requires p53 to kill cells. Of

course if there are a large proportion of cells that have some p53 it

would work on them, but what would remain are the resistant cells. It

is conceivable that there is some p53 being produced by the other

chromosome, but the experience is that where one p53 gene is lost,

the other is mutated. This is certainly so for those with unmutated

IgVH genes, though some patients with mutated IgVH genes have an

intact p53 gene on the other chromosome. In my experience these

patients smoulder and do not require treatment. Since Dave's disease

does require treatment I am guessing that the other p53 gene is

inactivated. There are formal tests that can determine this, but

these are the province of research laboratories, and not generally

available. "

I like your tenacity. I think it's good to keep probing - - you never

know. In light of this Dave, who did your IgVh testing & where was it

done? What was the result, i.e., what family: VH-1, 2, 3, 4, 5, 6, 7?

Who did your ZAP-70 test & where was it done? What clone was used,

e.g. clone 2F3.2, 1E7.2 (coupled with ALEXA-488?), et cetera? What

was/is your CD38 percentage?