N-terminally truncated hst-1 is a platelet-increasing factor

A method of increasing platelets in mammals which comprises administering to mammals an effective amount of a heparin-binding secretory transforming factor 1 protein (hst-1) having an N-terminal deletion of 27 amino acids.

FIELD OF THE INVENTION 
The present invention relates to a platelet-increasing agent containing a 
heparin-binding secretory transforming factor (hst-1) or a mutein thereof. 
BACKGROUND OF THE INVENTION 
Platelets play an important role in the promotion of thrombus formation and 
blood coagulation, which takes place in the course of hemostasis, in which 
the bleeding caused by the breakage of blood vessels naturally stops. In 
humans, the platelets are released in the blood from megakaryocytes 
produced by differentiation from myeloid stem cells through megakaryocyte 
precursor cells. 
A reduction in the number of platelets can be caused by thrombocytopenia, 
or by administration of anticancer drugs or irradiation with radioactive 
rays in treating cancers, which can result in serious consequences. 
However, no effective platelet-increasing agent has so far been 
discovered. 
Heparin-binding secretory transforming factor gene (hst-1 gene) is a 
transforming gene, which has been isolated from the tissue of human 
stomach cancer [H. Sakamoto et al., Proc. Natl. Acad. Sci., U.S.A., 83, 
3997 (1988)]. The gene product thereof shows some homology to fibroblast 
growth factor (FGF), one of cell growth factors, in structure and 
biological activity [T. Yoshida et al., Proc. Natl. Acad. Sci., U.S.A., 
84, 7305 (1987) and K. Miyagawa et al., Oncogene, 3, 383 (1988)]. The 
hst-1 gene has been isolated not only from stomach cancer tissue, but also 
from the tissues of colon cancer, hepatic cancer and Kaposi sarcoma of 
patients suffering AIDS [T. Koda et al., Jpn. J. Cancer Res. (Gann), 78, 
325 (1987), H. Nakagawa et al., Jpn. J. Cancer Res. (Gann), 78, 651 
(1987), Y. Yuasa et al., Jpn. J. Cancer Res. (Gann), 78, 1035 (1987), and 
P. Delli Bovi et al., Cell, 50, 729 (1987)]. This gene has been clasified 
along with basic FGF, acidic FGF, int-2 gene, etc. as forming the FGF 
faimily. The gene isolated from the above-mentioned Kaposi sarcoma, which 
is identical to hst-1 is also called K-FGF. 
The nucleotide sequence of the hst-1 gene has already been reported [M. 
Taira et al., Proc. Natl. Acad. Sci. U.S.A., 84, 2980 (1987), and T. 
Yoshida et al., Proc. Natl. Acad. Sci. U.S.A., 84, 7305 (1987)]. These 
reports provide the gene product deduced therefrom and the constituent 
amino acids of the hst-1 protein. 
No effective platelet-increasing agent has so far been discovered, and the 
properties and biological activity of the hst-1 are unknown in many 
respects. It would be desirable to have an effective platelet-increasing 
agent. It would also be desirable to have such an agent that could readily 
be prepared. 
SUMMARY OF THE INVENTION 
The present inventors have extesively searched for substances whose cells 
produce factors that exhibit effective platelet-increasing action on known 
cytokines. As a result, the present inventors have discovered that hst-1 
prepared by the recombinant DNA technique or hst-1 muteins that are 
similar therewith in activity show growth promoting activity for 
megakaryocytes (MK-CSF activity) sufficient to increase the number of 
peripheral platelets. Further investigations based on these findings 
resulted in the present invention. 
According to the present invention, there are provided (1) a method of 
increasing platelets in mammals which comprises administering to mammals 
an effective amount of a heparin-binding secretory transforming factor 1 
protein (hst-1) or a mutein thereof; (2) the method as described in (1) in 
which said mutein is a deletion type mutein; (3) the method as described 
in (2) wherein said mutein is lacking at least one amino acid or more 
amino acids from the N-terminus of SEQ ID NO:2; (4) the method as 
described in (2) wherein said mutein is lacking up to 47 amino acids of 
the N-terminal sequence of SEQ ID NO:2; (5) the method as described in (2) 
wherein said mutein is lacking up to 27 amino acids of the N-terminal 
sequence of SEQ ID NO:2; and (6) the method as described in (2) wherein 
said-mutein is lacking 27 amino acids of the N-terminal sequence of SEQ ID 
NO:2.