**7. The cholesterol and the treatment with anti-CD20 monoclonal antibodies**

It has been noted that the loss of CH is responsible for the decrease in the number of sites that can fix some monoclonal antibodies, including CD20. CH depletion or Shiga-like toxin binding have been causes of disruption of CD20 localization, but not of CD77 in lipid rafts. (Jarvis et al., 2007)

DXL625 is an anti-CD20 monoclonal antibody, capable of causing independently in vitro apoptosis of a lymphoma B cells line. This apoptosis is inhibited by the loss of membrane CH or of chelation of extracellular calcium, fact that underlines the role of lipid raft and calcium in this process. (Bingaman et al., 2010)

Many lymphoproliferations with B cells have indication of treatment with rituximab, an anti-CD20 antibody. The inhibitor therapeutic effect of rituximab occurs at the same time as the decrease of CH deposits from lipid rafts, with decreased B-cell receptor relocation to lipid rafts structures, and with the disruption of the expression of BCR immunoglobulin, lowering it. (Kheirallah et al., 2010)

**6. Experimental and clinical observations on cholesterol metabolism disorder**  ABCA1 and ApoA-I are responsible for the efflux of CH in human monocyte leukemia cell line derived foam cells. This decrease of the concentration of CH can be enhanced by administration of rosiglitazone. (Lü et al., 2010) Animals fed on alternate days have showed lower incidence of lymphomas, after tumor inoculation have had higher survival, and some types of cells have proliferated more slowly. It seems that this diet in humans would favor increased levels of HDL-cholesterol and lower those of triacylglycerol. (Varady et al., 2007) It was found that ether phospholipid edelfosine is able to accumulate and selectively destroy mantle cell lymphoma and CLL cells, underlining the importance of the action on lipid rafts and Fas/CD95 for the therapy of these lymphoproliferations. CH depletion is involved in lipid

Some clinical observations on the presence of dyslipidemia in patients with malignant

hypercholesterolemia

significantly higher in patients who completed the treatment for NHL than in those who completed ALL

low serum levels of HDL-

decrease

therapy

cholesterol

graft versus host disease

Lim et al., 2007 NHL serum HDL-cholesterol

Gokhale et al., 2007 NHL serum total CH level was

raft disruption and in the diminishing of drug captation. (Mollinedo et al., 2010)

**Author Disease Dyslipidemia** 

lymphoma

Table 1. Examples of dyslipidemia in patients with malignant hemopathies.

Helman et al., 2011 MALT + obesity hypercholesterolemia

**7. The cholesterol and the treatment with anti-CD20 monoclonal antibodies**  It has been noted that the loss of CH is responsible for the decrease in the number of sites that can fix some monoclonal antibodies, including CD20. CH depletion or Shiga-like toxin binding have been causes of disruption of CD20 localization, but not of CD77 in lipid rafts.

DXL625 is an anti-CD20 monoclonal antibody, capable of causing independently in vitro apoptosis of a lymphoma B cells line. This apoptosis is inhibited by the loss of membrane CH or of chelation of extracellular calcium, fact that underlines the role of lipid raft and

Many lymphoproliferations with B cells have indication of treatment with rituximab, an anti-CD20 antibody. The inhibitor therapeutic effect of rituximab occurs at the same time as the decrease of CH deposits from lipid rafts, with decreased B-cell receptor relocation to lipid rafts structures, and with the disruption of the expression of BCR immunoglobulin,

hemopathies are presented in Table 1.

Inamoto et al., 2005 ALL + cholestasis from

Garg et al., 2011 intravascular large B cell

MALT = mucosa-associated lymphoid tissue lymphoma

calcium in this process. (Bingaman et al., 2010)

lowering it. (Kheirallah et al., 2010)

(Jarvis et al., 2007)

The first monoclonal antibody that was approved for the treatment of B-cell lymphoproliferative malignancies was rituxan, a chimeric monoclonal anti-CD20 antibody. It has been observed that the monoclonal antibody attachment to CD20 produces a redistribution of these antigens to lipid rafts, which are specialized membrane microdomains. If rituxan is not used, the CD20 antigen affinity to lipid rafts is small. Intracellular calcium entry and apoptosis have been completely eliminated experimentally by extracting CH, which has led to the destruction of the integrity of lipid raft structures and to the dissociation of CD20 antigen from a fraction that is resistant to Triton X-100. From this it results that for the activation of caspase induced by CD20- lipid rafts appear to have an essential role. (Janas et al., 2005)

In multidrug resistance two populations of P-glycoprotein (P-gp) are involved. One is located in the membrane regions that are resistant to detergent; it has optimal P-gp ATPase activity; the verapamil can activate it and the orthovanadate can inhibit it almost entirely. The other population is located in another part of the membrane; it has less activity than Pgp ATPase of the first population; the verapamil can inhibit it, and its sensitivity to the orthovanadate is less. The first population of Pgp is surrounded by deposits of CH that may have the role to stimulate the P-gp ATPase activity, but the CH near the second population of Pgp does not seem to have such a role. (Barakat et al., 2005)

Rituximab induced apoptosis may be diminished by depletion of membrane deposits of CH, which does not allow the association to the detergent-insoluble lipid rafts of the antigen hypercrosslinked CD20. Under the action of rituximab, the antibody-bound CD20, found in lipid rafts in a high-affinity structure, activates src family kinases, interfering with the signal-transmission mechanism, which it inhibits. (Unruh et al., 2005)

Besides their CH-lowering effects, statins have pleiotropic effects, including the antileukemic ones observed in vitro and in vivo (Sassano et al., 2009), but they disrupt the binding (Winiarska et al., 2008) and the antitumour activity of rituximab (Ennishi et al., 2010), as a consequence of the changing of the antigen CD20 conformation (Ennishi et al., 2010; Winiarska et al., 2008). Statins interfere with the detection of CD20 as well as the antilymphomatous function of the rituximab (Winiarska et al., 2008). But in a study that analyzed the progression-free survival in 3 years and overall survival in a group of patients with diffuse large B-cell lymphoma, including some patients who were taking statins, it was found that there were no statistically significant differences, fact that advocates the idea that statins used in clinical treatment do not alter the prognosis of patients with diffuse large Bcell lymphoma under R-CHOP treatment. (Ennishi et al., 2010)
