Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 376-377
CORRESPONDENCE
Paradoxical Pro-Kaposi's Sarcoma Activity of
Preparations of Human Chorionic Gonadotropin
 |
LETTER |
To the Editor:
We read with interest the report by Massood et al1 on the
source of the anti-Kaposi's sarcoma (KS) activity observed in human
chorionic gonadotropin (hCG) commercial preparations.2 The
authors reported that a naturally occurring urinary dimer of 32 kD,
known as antineoplastic urinary protein (ANUP), had a strong anti-KS
activity that was still distinct from the activity observed in hCG
preparations. Their observation highlights the complexity of crude
preparations as well as the hazards relative to their clinical use.
Commercial preparations of hCG available in Belgium are Pregnyl
(Organon, Oss, The Netherlands) and Profasi (Serono, Aubonne, Switzerland). We investigated the effect of these preparations on
KS-derived spindle cells, established as reported by us and others.3,4 These cells were obtained from 1 patient with sporadic KS, from 1 renal transplant recipient, and from 2 acquired immunodeficiency syndrome patients. They overexpress the Bcl-2 protein
and constitutively produce a 92-kD type IV collagenase, which suggests
that they have a malignant potential.4,5 They did not react
for the CD34 endothelial cell marker, whose detection on cultured
KS-derived cells remains controversial.3,4,6,7 The hCG
preparations were also tested on the immortalized KS cell line KS
Y-18 (kindly provided by Dr Y. Lunardi-Iskandar, Baltimore, MD). Unexpectedly, we
observed that all the tested lots of Pregnyl (lots no. 96H06 96D01,
96H06 96D10, and 97C18 96K21) had a net promitotic activity on the
KS-derived spindle cells, independently of their epidemiological setting. By contrast, these preparations did not affect the growth of
the immortalized KS Y-1 cell line. Neither Profasi nor recombinant hCG
(gift from Dr G. Hennen, Liège, Belgium) modified
the cell growth of any of the studied cell type (Fig
1).
View larger version (22K):
[in this window]
[in a new window]
| Fig 1.
Effect of Pregnyl (lot 96H06 96D10) on the growth of
AIDS-KS cells derived from a nodular KS lesion ( ) and from a papular
KS lesion ( ) and on the growth of the immortalized KS Y-1 cell line
( ) (A). The cells were seeded at 3 × 103 cells
(1.5 × 103 for KS Y-1 cells) per well in 96-well
microplates and treated with increasing concentrations of Pregnyl. The
cell counts were determined on day 7 with a Coulter Counter (Coulter,
Hialeah, FL). Results are expressed as means (columns) ± SE (bars) of three independent experiments performed in duplicate.
**P < .01, significant difference from control (ie,
10 ± 2 × 103 cells per well for the KS-derived
spindle cell cultures and 85 ± 15 × 103 cells per well
and for the immortalized KS Y-1 cell line). Experiments using other
lots of Pregnyl (96H06 96D01 and 97C18 96K21) and experiments performed
on spindle cells derived from sporadic and iatrogenic KS yielded
similar results. Effect of Profasi (lot 96E10 95L08) on the growth of
the same cell types in identical culture conditions (B). Similar
results were also obtained when investigating [3H]
thymidine incorporation instead of cell count (data not shown).
|
|
To our knowledge, no data have yet been reported on `paradoxical'
stimulation of KS cell growth by commercial hCG preparations. These
findings raise the problem of the heterogeneous composition of
clinical-grade hCG preparations. Crude hCG preparations are obtained
from human pregnancy urine. They are tested for transmitted infectious
agents, such as human immunodeficiency virus or hepatitis B virus, and contain a variety of hCG-related molecules as well as a
mixture of biological contaminant substances. Several variables, including collection of urine from women at different gestational ages
and from various latitudes (involving different environmental and
genetic background), different modes of urine conservation, extraction,
and purification, may make that a commercial preparation of hCG totally
differs from another preparation in terms of biological activities.9 The absence or the inactivation
of the anti-KS activity in certain commercial preparations of hCG could
conciliate the present data with the poor clinical response observed in
some clinical trials,10 stressing the need for the
characterization of the anti-KS hCG-associated factors
(HAF)11 and the availability of monoclonal antibodies to
detect them. Because certain clinical-grade hCG preparations could not
only lack the ability to control KS, but also contain some contaminant
KS growth factor(s), we suggest a cautious use of these preparations in
clinical practice.
Thierry Simonart
Department of
Dermatology
Philippe Hermans
Jean-Paul Van Vooren
Department of Internal Medicine
Sylvain Meuris
Human
Reproduction Research Unit
Erasme University Hospital
Brussels,
Belgium
| |
REFERENCES |
1.
Massood R, McGarvey ME, Zheng T, Cai J, Arora N, Smith DL, Sloane N, Gill PS:
Antineoplastic urinary protein inhibits Kaposi's sarcoma and angiogenesis in vitro and in vivo.
Blood
93:1038, 1999[Abstract/Free Full Text]
2.
Gill PS, Lunardi-Yskandar Y, Louie S, Tulpule A, Zheng T, Espina BM, Besnier JM, Hermans P, Levine AM, Bryant JL, Gallo RC:
The effects of preparations of human chorionic gonadotrophin on AIDS-related Kaposi's sarcoma.
N Engl J Med
335:1261, 1996[Abstract/Free Full Text]
3.
Benelli R, Repetto L, Carlone S, Parravicini C, Albini A:
Establishment and characterization of two new Kaposi's sarcoma cell cultures from an AIDS and a non-AIDS patient.
Res Virol
145:251, 1994[Medline]
[Order article via Infotrieve]
4.
Simonart T, Degraef C, Noel JC, Fokan D, Zhou L, Pradier O, Ducarme M, Schandene L, Van Vooren JP, Parent D, Heenen M:
Overexpression of Bcl-2 in Kaposi's sarcoma-derived cells.
J Invest Dermatol
111:349, 1998[Medline]
[Order article via Infotrieve]
5.
Blankaert D, Simonart T, Van Vooren JP, Parent D, Liesnard C, Farber CM, Marique T, Werenne J:
Constitutive release of metalloproteinase-9 (92-kD type IV collagenase) by Kaposi's sarcoma cells.
J Acquir Immune Defic Syndr Hum Retrovirol
18:203, 1998[Medline]
[Order article via Infotrieve]
6.
Kaaya EE, Parravicini C, Ordonez C, Gendelman R, Berti E, Gallo RC, Biberfeld P:
Heterogeneity of spindle cells in Kaposi's sarcoma: comparison of cells in lesions and in culture.
J Acquir Immune Defic Syndr Hum Retrovirol
10:295, 1995[Medline]
[Order article via Infotrieve]
7.
Masood R, Cai J, Zheng T, Smith DL, Naidu Y, Gill PS:
Vascular endothelial growth factor/vascular permeability factor is an autocrine growth factor for AIDS-Kaposi's sarcoma.
Proc Natl Acad Sci USA
94:979, 1997[Abstract/Free Full Text]
8.
Lunardi-Iskandar Y, Gill P, Lam VH, Zeman RA, Michaels F, Mann DL, Reitz MS, Kaplan M, Berneman ZN, Carter D, Bryant JL, Gallo RC:
Isolation and characterization of an immortal neoplastic cell line (KS Y1) from AIDS-associated Kaposi's sarcoma.
J Natl Cancer Inst
87:974, 1995[Abstract/Free Full Text]
9.
Nagy AM, Meuris S, Robyn C:
Inventory of the molecular heterogeneity of purified human chorionic gonadotrophin preparations as revealed by immunoelectrotransfer.
Med Sci Res
17:771, 1989
10.
Tirelli U, Tavio M, Giacca M, De Paoli P:
Human chorionic gonadotropin in the treatment of HIV-related Kaposi's sarcoma.
AIDS
11:387, 1997[Medline]
[Order article via Infotrieve]
11.
Samaniego F, Bryant JL, Liu N, Karp JE, Sabichi AL, Thierry A, Lunardi-Yskandar Y, Gallo RC:
Induction of programmed cell death in Kaposi's sarcoma cells by preparations of human chorionic gonadotropin.
J Natl Cancer Inst
91:135, 1999
