Growth factors - Pharmaceutical Biotechnology: Concepts and Aapplications - page 280

10.2.6.2 Chronic disease and cancer chemotherapy

Anaemia often becomes a characteristic feature of several chronic diseases, such as rheumatoid
arthritis. In most instances this can be linked to lower than normal endogenous serum EPO levels
(although in some cases a defi ciency of iron or folic acid can also represent a contributory factor).
Several small clinical trials have confi rmed that administration of EPO increases haematocrit and
serum haemoglobin levels in patients suffering from rheumatoid arthritis. A satisfactory response
in some patients, however, required a high-dose therapy that could render this therapeutic approach
unattractive from a cost:benefi t perspective.
Severe, and in particular chronic, infection can also sometimes induce anaemia, which is often
made worse by drugs used to combat the infection. For example, anaemia is evident in 8 per cent of
patients with asymptomatic HIV infection. This incidence increases to 20 per cent for those with
AIDS-related complex, and is greater than 60 per cent for patients who have developed Kaposi's
sarcoma. Up to a third of AIDS patients treated with zidovudine also develop anaemia. Again,
several trials have confi rmed that EPO treatment of AIDS sufferers (be they receiving zidovudine
or not) can increase haematocrit values and decrease transfusion requirements.
Various malignancies can also induce an anaemic state. This is often associated with decreased
serum EPO levels, although iron defi ciency, blood loss or tumour infi ltration of the bone marrow
can be complicating factors. In addition, chemotherapeutic agents administered to this patient
group often adversely affect stem cell populations, thus rendering the anaemia even more severe.
Administration of EPO to patients suffering from various cancers/receiving various chemo-
therapeutic agents yielded encouraging results, with signifi cant improvements in haematocrit
levels being recorded in approximately 50 per cent of cases. In one large US study (2000 patients;
most receiving chemotherapy) s.c. EPO administration of an average of 150 IU kg 1 , three times
weekly, for 4 months, reduced the number of patients requiring blood transfusions from 22 per
cent to 10 per cent. Improvement in the sense of well-being and overall quality of life was also
noted. The success rate of EPO in alleviating cancer-associated anaemia has varied in different
trials, ranging from 32 per cent to 85 per cent.
On a more cautionary note, the EPO receptor is expressed not only by specifi c erythrocyte
precursor cells, but also by endothelial, neural, and myeloma cells. Concern has been expressed
that EPO, therefore, might actually stimulate growth of some tumour types, particularly those
derived from such cells. To date, no evidence ( in vitro or in vivo ) has been obtained to support this
hypothesis.

10.2.7 Thrombopoietin

Human TPO is a 332 amino acid, 60 kDa glycoprotein, containing six potential N-linked
glycosylation sites. These are all localized towards the C-terminus of the molecule. The N-terminal
half exhibits a high degree of amino acid homology with EPO and represents the biologically
active domain of the molecule.
TPO is the haemopoietic growth factor now shown to be the primary physiological regulator
of platelet production. This molecule may, therefore, represent an important future therapeutic
agent in combating thrombocytopenia, a condition characterized by reduced blood platelet levels.
The most likely initial TPO therapeutic target is thrombocytopenia induced by cancer chemo- or