Abstract
Chromogranin A (CgA) is present in high concentrations in enterochromaffin cells, where it is co-localised with serotonin in the storage granules. Plasma CgA has been reported to mark emesis and serotonin release associated with cisplatin treatment. However, it is not known whether plasma CgA could be an indicator of emesis and of serotonin release in patients receiving non-cisplatin chemotherapies. Therefore, in this study we evaluated, in cancer patients, the temporal relationships between the increases in plasma CgA and urinary 5-hydroxyindoleacetic acid (5-HIAA) and the development of vomiting following dacarbazine, nitrogen mustard and cyclophosphamide treatments. Metoclopramide was used as antiemetic. With dacarbazine, nitrogen mustard and cyclophosphamide the median time to the onset of emesis was 2.3, 2.8 and 5.3 h and the duration of intense emesis was 3, 2 and 6 h respectively. Plasma CgA and urinary 5-HIAA increased after dacarbazine- and nitrogen mustard-based chemotherapies, with maximal increases between 4 and 6 h after initiation of drug infusion. The time course for the increases in plasma CgA paralleled that of urinary 5-HIAA and the period of intense emesis. A highly significant (P = 0.0009) positive correlation (r = 0.68) was found between the increases in plasma CgA and in urinary 5-HIAA. Cyclophosphamide treatment was not associated with increases in plasma CgA and in urinary 5-HIAA, despite inducing emesis; this indicates that the increases in CgA and 5-HIAA after dacarbazine and nitrogen mustard are not due to the act of vomiting per se. In summary, plasma CgA is a marker of serotonin release (most likely from enterochromaffin cells) after dacarbazine and nitrogen mustard-based chemotherapies, exocytosis being the most likely mechanism for the release of serotonin. Serotonin released from enterochromaffin cells seems to trigger the emetic response to dacarbazine and nitrogen mustard; however, cyclophosphamide may release serotonin from a different pool (enteric serotonin neurons and/or CNS serotonin?).
Highlights
The effects of dacarbazine-based chemotherapies on plasma Chromogranin A (CgA) levels of urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion were studied in seven patients with malignancies (Table I)
Significant increases in plasma CgA were already present at 3 h (47% increase above baseline), and maximal increases (96% ± 21 % increase above baseline levels; P
CgA is present in very high concentrations in the gastrointestinal tract (O'Connor et al, 1983; Facer et al, 1985; Varndell et al, 1985) and immunohistochemical studies have demonstrated that enterochromaffin cells are an important source of this protein (Cetin and Grube, 1991; Bargsten and Grube, 1992)
Summary
A total of 20 patients with histologically confirmed cancer, 18 years of age or older, who had not received previous chemotherapy, and had a Karnofsky performance score of at least 60% were enrolled in the study. Patients were excluded from the study if they had abnormal liver or renal function tests, or had any nausea and vomiting within 24 h of the study period. Patients who received abdominal or pelvic radiation therapy within 48 h before or during the day of the study were excluded. Written informed consent was obtained from all patients. The study protocol was evaluated e04 and accepted by the Institutional Review Board at participating institutions, and conducted at the medical oncology divisions of the Luis Razetti and Padre Machado Hospitals of the city of Caracas.
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