Sex differences in transport of the organic anion (OA) substrate p-aminohippurate (PAH) and the organic cation (OC) substrate tetraethylammonium (TEA) have been recognized for some time. In the rat kidney, androgens up-regulate and estrogens down-regulate PAH and TEA transport, which correlate with similar changes in mRNA and protein expression for the renal basolateral membrane transporters organic anion transporter (Oat) 1 and organic cation transporter (Oct) 2. However, these sex differences are not readily demonstrated in other species. The present study characterizes the kinetics of basolateral membrane PAH, estrone sulfate (ES), and TEA uptake in renal proximal tubule (RPT) suspensions isolated from female and male rabbits to compare functional expression of transport with mRNA and protein expression for rbOat1, rbOat3, and rbOct2. Although rbOat1-rbOat3 mRNA expression exhibited developmental differences, no sex differences in mRNA levels were observed. Oat1 and Oat3 protein expression in RPT suspensions also was similar between adult female and male rabbits. In contrast, rbOct1 and rbOct2 mRNA levels did not show developmental differences, but rbOct2 mRNA expression was greater in adult male than female rabbits. However, the sex difference in rbOct2 mRNA level did not translate to rbOct2 protein expression. Importantly, functional expression of Oat1, Oat3, and Oct2 transport as measured by kinetics (J max and K t ) of PAH, ES, and TEA uptake was similar between adult male and female rabbits, and correlated with rbOat1, rbOat3, and rbOct2 protein expression. Thus, unlike rodents, rabbit renal OA and OC transport does not exhibit sex differences, pointing to the need for caution in extrapolating transport-related sex differences between species.

High-dose chemotherapy with autologous HSCT is potentially curative in patients (pts) with relapsed or refractory lymphoma. However, the optimal pre-HSCT conditioning regimen is not known. Mitoxantrone, an antineoplastic agent that inhibits DNA synthesis by inhibition of topoisomerase II and by intercalation into the DNA molecule, has shown activity in several hematological malignancies, including NHL and HD. Recent evidence suggests that mitoxantrone may be more cardiotoxic than previously recognized. We evaluated a novel mitoxantrone-containing preparative regimen for autologous HSCT in pts with relapsed or refractory NHL or HD. Between 1989 and 1996, 59 pts (31 NHL, 28 HD) with chemotherapy refractory or relapsed lymphoma were enrolled. The median age was 36 yr (range, 10–60); 38 pts were male, and 21 were female. Cohorts of pts received escalating doses of mitoxantrone (24–60 mg/m2) on day -8, etoposide 1800 mg/m2 on day -8, cyclophosphamide 1800 mg/m2 on days -7 through -3, and carmustine 300 mg/m2 on day -3. Autologous stem cells were infused on day 0. G-CSF was begun day +3. Patients with areas of bulky disease pre-transplant underwent consolidative involved field radiotherapy, but no earlier than day +14. Results: Patients received mitoxantrone according to the following dose escalation: 24 mg/m2 (n=3), 30 mg/m2 (n=1), 36 mg/m2 (n=3), 42 mg/m2 (n=3), 48 mg/m2 (n=48), 54 mg/m2 (n=1). Median time to neutrophil engraftment was 13 days (range, 8–60 days) and median time to platelet engraftment was 17 days (range, 5–51 days). Non-hematologic toxicities were measured according to the NCI CTCAE Version 3.0. Toxicities greater than grade 2 included mucositis in 35 patients (24 grade 3, 11 grade 4), nausea and vomiting in 9 (6 grade 3, 3 grade 4), diarrhea in 5 (all grade 3), hepatotoxicity in 5 (all grade 3), and nephrotoxicity in 14 (12 grade 3, 2 grade 4). The dose limiting toxicity for mitoxantrone was cardiac toxicity, and the maximum tolerated dose was 48 mg/m2. Early cardiac toxicity was observed in 2 patients: one was withdrawn from the clinical trial before HSCT due to cardiotoxicity, and one patient died on day +8 of cardiotoxicity. Late (≥ 100 days after HSCT) nonfatal cardiac toxicity included cardiomyopathy (n=1), and cardiac tamponade (n=1). For all patients, the 5-year overall survival post HSCT was 51%, and 5-year disease free survival was 37%. Median time to relapse was 24 mo (range, 3.6–71.9 mo) after HSCT. For the 31 patients with NHL, the 5-year overall survival was 48% and 5-year disease-free survival was 35%. For the 28 patients with HD, the 5-year overall survival was 50% and the 5-year disease-free survival was 39%. Conclusion: The addition of mitoxantrone to standard preparative regimens may improve outcomes in patients with relapsed or refractory lymphoma, however further investigations of this agent in pre-HSCT conditioning regimens must carefully consider strategies that minimize the risks of cardiac toxicity.