Using non-invasive methods to characterize gonadal hormonal patterns of southern three-banded armadillos (Tolypeutes matacus) housed in North American zoos.

Understanding the basic reproductive biology and limitations to successful breeding of the southern three-banded armadillo (Tolypeutes matacus) is necessary to maintain viable zoo populations. Our objectives were to: 1) describe the reproductive biology using non-invasive, fecal hormone analysis; 2) assess influence of season on gonadal hormonal patterns in both the sexes; 3) characterize reproductive cyclicity and pregnancy in the female; and 4) characterize the onset of sexual maturity in males. Nineteen armadillos were monitored including: 13 (7 males, 6 females) from Lincoln Park Zoo and six (3 males, 3 females) from San Antonio Zoological Garden. Fecal samples (n=5220; 275/animal/yr) were collected 5 to 7 times a week for 1 year. Hormones were extracted from feces and analyzed for progestagen (females) and androgen (males) metabolite concentrations using enzyme immunoassays. Mean estrous cycle length (26.4±1.3 days) did not vary (P<0.05) among individuals (n=9). Mean gestation length (n=3) was 114.0±0.6 days long with mean fecal progestagen metabolites increasing 10-fold during pregnancy. Seasons did not influence (P<0.05) fecal androgen or progestagen metabolites. These data can assist with management decisions, which will directly affect the success of this species in zoos.

Phase I study of the effects of renal impairment on the pharmacokinetics and safety of satraplatin in patients with refractory solid tumors.

BACKGROUND: Satraplatin is an oral platinum analog with demonstrated activity in a range of malignancies. The current study was designed to evaluate the effect of varying degrees of renal impairment on the safety and pharmacokinetics (PKs) of satraplatin. PATIENTS AND METHODS: Patients with advanced solid tumors, refractory to standard therapies, were eligible. The study included four cohorts of patients with varying levels of renal function, and eight patients per cohort: Group 1 (G1) = normal renal function; G2 = mild renal impairment [creatinine clearance (CrCl) 50-80 ml/min]; G3 = moderate impairment (CrCl 30 to <50 ml/min); G4 = severe impairment (CrCl <30 ml/min). Satraplatin was administered orally at 80 mg/m(2)/day on days 1-5 every 35 days. RESULTS: A total of 32 patients were enrolled, 8 patients in each renal function group. Each group tolerated the dose of 80 mg/m(2)/day on days 1-5 every 35 days without the need for dose deescalation. The most common adverse events were fatigue (63%), nausea (56%), diarrhea (53%), anorexia (47%), constipation (38%), vomiting (28%), anemia, dyspnea, and thrombocytopenia (25%). There were no dose-limiting toxic effects in any study group. There was increased exposure to plasma platinum and plasma ultrafiltrate platinum in patients with moderate to severe renal impairment. CONCLUSIONS: Satraplatin PKs was altered in patients with renal impairment. However, a corresponding increase in satraplatin-related toxic effects was not observed.

A phase I study of an oral simulated FOLFOX with high dose capecitabine.

BACKGROUND: A phase I study of high-dose capecitabine given over 2 days, along with oxaliplatin, bolus 5FU and leucovorin (LV), was designed to simulate FOLFOX6 without the need for infusional 5FU. METHODS: Schedule A included oxaliplatin 100 mg/m(2), 5FU 400 mg/m(2), and LV 20 mg/m(2) (all given IV on days 1 and 15, 28 day cycle). Capecitabine was administered orally every 8 h x 6 doses, days 1 and 15. Schedule B excluded 5FU and LV, maintaining oxaliplatin and capecitabine. Pharmacokinetics were performed for capecitabine for 6 patients on each schedule. RESULTS: 36 patients were treated. The dose-limiting toxicities seen included nausea, dehydration, fatigue, hypotension and confusion. Minimal palmar-plantar erythrodysesthesia was seen. Myelosuppression was common, but not a dose limiting toxicity. The pharmacokinetic parameters for capecitabine were unaltered. CONCLUSION: Using capecitabine to mimic FOLFOX6 is feasible and well tolerated with a toxicity profile that differs from standard 14-day capecitabine dosing, with less palmar-plantar erythrodysesthesia. The phase II dose for capecitabine in combination with oxaliplatin, 5FU, and LV is 1,500 mg/m(2)/dose or 2,250 mg/m(2)/dose in the absence of bolus 5FU/LV.

Heat shock protein antibodies in sarcoma patients undergoing 41.8 degrees C whole body hyperthermia.

Previous in vitro studies of sarcoma and normal cell lines exposed to 41.8 degrees C (x 60 min) demonstrated selective increased expression of members of the heat shock protein (HSP) family 70 on the cell surface of the sarcoma cells only. One implication of these data relates to the clinical application of targeting a stress-inducible, tumor-specific immune response. We therefore elected to measure immune response parameters (i.e., serum antibodies against HSP70i, 60, and 27) in six patients with sarcoma using a Western blot technique. These study patients received one to four successive 41.8 degrees C whole-body hyperthermia (WBH) x 60-min treatments (given every 3 weeks). We also tested the serum of 10 untreated healthy control subjects for the same parameters. In all patients, baseline HSP antibody levels were detectable; in no case did WBH result in an increase in HSP antibodies. The serum of one patient with sarcoma demonstrated a strong nonfluctuating reaction against HSP27 before and after WBH that had no obvious correlation; this was not observed in the sera of the control subjects. This study suggests that WBH does not induce a B-cell response to HSP family 70 antigens; these data, however, do not exclude the possibility of NK cell activation due to HSP antigen presentation.

Optimization of chemotherapy administration for clinical 41.8 degrees C whole body hyperthermia.

Preclinical data is consistent with the concept that the timing of chemotherapy during radiant heat-whole body hyperthermia (WBH) should affect therapeutic index. In order to test this hypothesis, a controlled clinical investigation was initiated. Patients received carboplatin (CBDCA) on an early or late schedule with respect to achieving target temperature (i.e. 41.8 degrees C) in alternating treatment cycles. The first cycle was randomized between patients regarding the early or late schedule for two planned sets per patient (i.e. four cycles). Ifosfamide, etoposide and granulocyte colony stimulating factor were delivered during all cycles with a standardized schedule. A total of 53 cycles involving 17 patients were analyzed. Detailed toxicity evaluation (i.e. delay in therapy secondary to thrombocytopenia, need for platelet transfusions, and days of hospitalization) taken collectively demonstrated a statistically and clinically significant advantage to delivering CBDCA 10 min after target temperature, during the plateau phase of WBH.

In vitro studies of the hyperthermic enhancement of activated ifosfamide (4-hydroperoxy-ifosfamide) and glucose isophosphoramide mustard.

PURPOSE: To study the effect of hyperthermia on the cytotoxicity of glucose isophosphoramide mustard (D-19575), a derivative of ifosfamide, which does not require activation and preclinically demonstrates less nephrotoxicity and myelosuppression than ifosfamide. METHODS: In vitro studies (using a crystal violet cell survival assay) of the interaction of hyperthermia with D-19575, as well as the activated form of ifosfamide (4-hydroperoxy-ifosfamide, D-18851), were performed using L929 and OVCAR-3 cell lines held at various temperatures (i.e. 37 degrees C (control), 40.5 degrees C, 41.8 degrees C, 42.5 degrees C, and 43 degrees C) for 65 min. RESULTS: The following thermal enhancement ratios (TER) were demonstrated: D-19575 in L929 1.2, 2.0 and 2.3 at 40.5, 41.8 and 42.5 degrees C, respectively; for D-18851 in L929 1.7 at 41.8 degrees C; for D-19575 in OVCAR-3 2.1, 3.2 and 3.3 at 40.5, 41.8 and 42.5 degrees C, respectively; for D-18851 in OVCAR-3 4.6 at 41.8 degrees C. CONCLUSION: The significant observed increase in cytotoxicity of D-19575 caused by hyperthermia taken together with its known preclinical toxicity profile, encourage its further preclinical and ultimately clinical testing, including its use with whole body and regional hyperthermia.

Dynamic changes in serum erythropoietin levels in solid tumour patients undergoing 41.8 degrees C whole body hyperthermia and/or chemotherapy.

Whole Body Hyperthermia (WBH) has been shown to have physiological effects on myeloid and megakaryocytic haematopoietic tissue via both cytokine induction, as well as hormonal changes. In order to extend this knowledge base to the erythroid cells, endogenous erythropoietin (EPO) levels were studied in 17 cancer patients receiving 41.8 degrees C WBH and/or chemotherapy, as well as in 53 anaemic and non-anaemic control patients. Pre-treatment EPO levels showed a 'blunted' EPO response in cancer patients compared to the control patients. Post-treatment data demonstrated a significant chemotherapy induced increase in EPO levels with a peak at 36 to 48 hours (independent of changes in haemoglobin) and 10 to 13 days post chemotherapy (simultaneously with a drop in haemoglobin levels). The early change in EPO levels was not influenced by the addition of 41.8 degrees C (x 60 min) WBH to the same chemotherapy regimen, i.e., ifosfamide, carboplatin, and etoposide. Taken collectively, our data show that endogenous EPO levels in cancer patients can be effected by chemotherapy (independent of changes in haemoglobin). This EPO response to chemotherapy is not impacted on by 41.8 degrees C WBH. A relevant secondary conclusion can also be derived from this investigation, i.e., caution should be exercised as to the use of EPO levels during chemotherapy as predictors of exogenous EPO efficacy.

Influence of circadian rhythm on 41.8 degrees C whole body hyperthermia induction of haematopoietic growth factors.

It has previously been reported by the authors that the induction of a series of cytokines by 41.8 degrees C Whole Body Hyperthermia (WBH), i.e., interleukin (IL)-1 beta, IL-6, IL-8, IL-10, tumour necrosis factor alpha, and granulocyte colony stimulating factor (G-CSF). As cytokine levels are known to fluctuate as a function of time, i.e. circadian rhythm, the influence of circadian time structure on specific haemotopoetic growth factors is studied, i.e. granulocyte macrophage colony stimulating factor (GM-CSF), G-CSF and IL-3. Samples derived from four cancer patients undergoing extracorporeal WBH resulted in the following observations: G-CSF is induced by WBH, but unaffected by circadian rhythm, IL-3 fluctuates with circadian rhythm, but is unaffected by WBH. Specifically, a biphasic temporal pattern of IL-3 (i.e. with a peak at 2:00 and 5:00 a.m. and a nadir concentration at 5:00 p.m.) was found by analysis of variance. GM-CSF was below the lower detection limit pre and post WBH. The data show the importance of measuring cytokines as a function of time to circumvent conflicting results in the inter-relationship of 'true' cytokine induction and circadian rhythm. The implications of the differential induction of G-CSF, GM-CSF, and IL-3 for myeloprotection after WBH are discussed.