Plasma kinetics of a cholesterol-rich microemulsion (LDE) in patients with Hodgkin's and non-Hodgkin's lymphoma and a preliminary study on the toxicity of etoposide associated with LDE.
BACKGROUND
Neoplastic diseases are often associated with low plasma low-density lipoprotein (LDL) cholesterol and diminished LDL clearance due to upregulation in cancer cells of the receptors that internalize the lipoprotein. Thus, it is possible to use LDL or cholesterol-rich microemulsions (LDE) that bind to LDL receptors as carriers of antineoplastic agents to concentrate those drugs into cancer tissues. Our aim was to determine whether LDL cholesterol concentration plus LDE increased clearance occur in lymphomas.


METHODS
The LDE labeled with [(3) H]-cholesteryl oleate was injected into four Hodgkin's and 12 non-Hodgkin's lymphoma patients and into 16 healthy control subjects and the LDE plasma residence time (RT) was determined from sequential plasma samples. Two volunteers with relapsed/refractory lymphoma were treated with 300 mg/m(2) body surface etoposide associated with LDE in six cycles at 3-week intervals.


RESULTS
The LDL cholesterol was lower in lymphoma patients than in controls (94+/-52 and 115+/-16 mg/dL, p=0.0362, respectively). The LDE RT was 49% smaller in lymphoma patients than in controls (RT=21.9 and 45.7 h; p=0.0134), with positive correlation between RT and LDL cholesterol. LDE-etoposide showed no considerable toxicity in all cycles in the two treated patients and the disease remained stable during the treatment.


CONCLUSIONS
Our results suggest that lymphomas overexpress LDL receptors that make room for using LDE as drug-targeting vehicle and that the LDE-etoposide preparation is suitable for patient use.
Pinheiro
Ketlin V
KV
Lipid Metabolism Laboratory, Heart Institute (InCor), University of São Paulo Medical School Hospital, Av. Dr. Eneas de Carvalho Aguiar, 44,1, subsolo, 05403-000, São Paulo, Brazil.
Hungria
Vania T M
VT
Ficker
Elisabeth S
ES
Valduga
Claudete J
CJ
Mesquita
Carlos H
CH
Maranhão
Raul C
RC
D000293:Adolescent; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D002788:Cholesterol Esters / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008078:Cholesterol, LDL / Q000378:metabolism; D004337:Drug Carriers / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D004655:Emulsions; D005047:Etoposide / Q000633:toxicity*; D005260:Female; D006689:Hodgkin Disease / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010865:Pilot Projects; D011973:Receptors, LDL / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D002788:Cholesterol Esters; D008078:Cholesterol, LDL; D004337:Drug Carriers; D004655:Emulsions; D011973:Receptors, LDL; C014409:cholesteryl oleate; D005047:Etoposide