Cisplatin preceded by concurrent cytarabine and hydroxyurea: a pilot study based on an in vitro model

Abstract

As previously reported, cytotoxic synergy is produced when clinically achievable concentrations of cytarabine (Ara-C) and hydroxyurea (HU) are used as potential inhibitors of in vitro DNA repair in cisplatin (cis-Pt)-treated human colon carcinoma cells. This pilot study was subsequently designed to duplicate the in vitro dose and schedule and to determine the toxicity of this three-drug combination in two cohorts of patients. 21 patients had received prior chemotherapy and 19 were not previously treated. All patients had refractory solid tumors. They received monthly cycles of an oral loading dose of 800 mg/m2 HU followed every 2 h by 6 oral doses of 400 mg/m2, a 12-h continuous infusion of 200 or 250 mg/m2/h Ara-C concurrent with the HU, and then 100 mg/m2 cis-Pt over 1 h. A total of 95 cycles were given with the expected toxicities of nausea and vomiting and fatigue but not major acute toxicity observed. Thrombocytopenia was significant but transient and was dose-limiting only for patients who had received prior therapy. The median platelet nadir after one cycle was 43,000/microliters for all patients and 67,000/microliters for those who had not undergone prior treatment. Azotemia was treatment-limiting in responding and stable patients, suggesting the possibility of synergistic nephrotoxicity. Interestingly, there were early transient rises in both uric acid and lactate dehydrogenase (LDH). Partial responses were seen in 9 of 32 patients with measurable disease and there was significantly improvement in 5 of 8 patients with only evaluable disease. The responses or improvement occurred in patients with non-small-cell lung cancer, breast carcinoma, glioblastoma, ovarian carcinoma, small-cell lung cancer, and mesothelioma. Of these 14 patients, 9 had failed prior chemotherapy regimens. Significantly, responses were observed in 3 of 8 patients who had previously received cis-Pt, suggesting that the HU/Ara-C combination modulated cis-Pt resistance. Because of these encouraging results, a second pilot study has been initiated with modifications dictated by the toxicity issues raised in this trial.

A Phase II study of cisplatin preceded by a 12-h continuous infusion of concurrent hydroxyurea and cytosine arabinoside (Ara-C) for adult patients with malignant gliomas (Southwest Oncology Group S9149)

“…High concentrations of cisplatin are found in brain tumors after intravenous administration [17], with activity of cisplatin noted in refractory disease [17,18,23]. Furthermore, one patient with GBM who had failed surgery, radiotherapy and high dose AZQ with auto BM rescue sustained a response to the 3-drug regimen in the first pilot study [1]. The 3-drug regimen was a logical choice given prior results with these drugs used separately, and in view of the possibility of re-creating in vivo the marked platinum sensitization achieved in vitro.…”

“…Cytosine arabinoside (Ara-C) and hydroxyurea (HU), in combination, inhibit the removal of platinum DNA adducts, and marked cytotoxic synergy has been demonstrated in very platinum-resistant HT29 colon carcinoma cells [21]. The HU (1 mM) and Ara-C (1 uM) drug levels required have been achieved in clinical pilot studies of the three-drug regimen [1,2].…”