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Combination chemotherapy with newer, more active drugs in patients with advanced and/or metastatic bladder cancer might show improved response rate and survival. Gemcitabine (GEM) and Epidoxorubicin (EPI) have demonstrated activity in this disease. In addition, experimental studies in vitro have shown that the two agents have additive-synergistic effects when used in combination. Our prior phase I dose-finding study in previously untreated patients with advanced or metastatic bladder cancer defined recommended doses for further trials of GEM 1000 mg/m2 and EPI 25 mg/m2 on days 1, 8 and 15 every 28 days. A phase II trial at this dose level was initiated in previously untreated patients to assess efficacy and toxicity. Eligible patients had measurable disease; Karnofsky performance status (PS) of > 40; no prior chemotherapy; and adequate bone marrow reserve, cardiac, hepatic and renal function. Thirty- one patients (22 males, 9 females) with median age of 64 (range 44-75) and median PS of 80 were accrued, and all were eligible. Twelve patients had T4N1-2 M0, 8 had lymph node only metastases, while 11 had visceral metastases (liver, bone, lung). A total of 181 cycles was administered (range 3-7 per patient). Major toxicities (WHO grade > or = 3) were: neutropenia in 5 patients, thrombocytopenia in 2 patients, and anemia in 2 patients. Three patients had febrile neutropenic episodes and only 3 patients required dose reduction. Grade 1-2 non-hematological toxicities included nausea/vomiting, stomatitis and alopecia. No cardiac toxicity was observed. Of the 30 response evaluable patients, 17 (57%) demonstrated a major response (3 complete and 14 partial) (95% CI: 39%-75%), 7 had stable disease (23%) and 6 progressed (20%). These preliminary results confirm the phase I observation that the combination of GEM--EPI is highly active in the treatment of advanced and metastatic bladder cancer with a favourable toxicity profile.

The neuroendocrine system modulates the immune response through neuropeptides and neurohormones, findings which point to the existence of a neuro-endocrine-immune system regulatory axis. At the same time, there is growing evidence that the pineal gland has anti-neoplastic properties, which include the action of its principal hormone, melatonin (MLT), on the immune system through the release of cytokines by activated T-cells and monocytes. The present study was carried out on 31 patients (19 males and 12 females, age range 46-73 years) with advanced solid tumors (7 gastric, 9 enteric, 8 renal, 5 bladder, 2 prostate) who either failed to respond to chemotherapy and radiotherapy or showed insignificant responses and were therefore shifted to MLT therapy (10 mg/die orally for 3 months). We obtained blood samples just before the start of MLT administration and after 30 days of therapy. Plasma was collected in EDTA tubes on ice, immediately centrifuged at 4 degrees C and stored frozen at -80 degrees C; samples were measured by immunoradiometric assays (Medgenix-Fleurus, Belgium) for tumor necrosis factor alpha (TNF), interleukin-1, 2 and 6 (IL-1, IL-2, IL-6) and interferon gamma (IFN). We used Student's paired t-test to compare each patient's cytokine circulating levels before and after MLT administration and found a significant differences (p < 0.05). After 3 months of therapy, none of our patients displayed adverse reactions to MLT or had to discontinue treatment. Nineteen patients (61%) showed disease progression. The other 12 (39%), however, achieved disease stabilization with no further growth of either the primary tumor or of secondaries; moreover, they experienced an improvement in their general well-being, in terms of Tchekmedyian's criteria, associated with a significative decrease of IL-6 circulating levels. These findings are consistent with the hypothesis that MLT modulates immune function in cancer patients by activating the cytokine system which exerts growth-inhibitory properties over a wide range of tumor cell types. Furthermore, by stimulating the cytotoxic activity of macrophages and monocytes, MLT plays a critical role in host defence against the progression of neoplasia.

Impairment of respiratory control in myocardial cells has been implicated in attempts to explain the cardiac toxicity of anthracycline antibiotics. This parameter has been found to correlate significantly with depletion of ATP and increase of Ca2+ intracellular concentration in rat heart slices. It has been suggested that 4'-deoxydoxorubicin and 4-demethoxydaunorubicin, whose molecular structures differ slightly from those of doxorubicin and daunorubicin, respectively, might be less cardiotoxic. The present study evaluates the effect in vitro of these new anthracycline derivatives (10 micrograms/ml) on endogenous respiration, measuring oxygen uptake in rat heart slices incubated for 60 min in a Warburg manometric apparatus at 38 degrees C. Mean oxygen uptake values +/- SE (microliter/mg d.w) were as follows: control condition 4.21 +/- 0.2; with doxorubicin 3.03 +/- 0.1; with 4-demethoxydaunorubicin 3.75 +/- 0.1; with 4'-deoxydoxorubicin 3.87 +/- 0.2. Thus, in terms of this parameter, 4'-deoxydoxorubicin and, to a lesser extent, 4-demethoxydaunorubicin are less cardiotoxic than doxorubicin. However, it is well to bear in mind that impairment of respiratory control is only one of the aspects of cellular damage that leads to anthracycline-induced cardiomyopathy.

Carnitine, a naturally occurring compound which is an important cofactor in the transport of fatty acids within inner mitochondria, aids myocardial cells in efficiently meeting energy requirements. L-Carnitine has been texted in this study as a possible protective agent against doxorubicin-induced cardiac toxicity. Rat heart slices were incubated with doxorubicin (14 micrograms/ml), L-carnitine (600 micrograms/ml), and L-carnitine plus doxorubicin for 60 min at 38 degrees C. Cellular oxygen uptake, ATP, intracellular Ca2+, and 14C-Leucine incorporation were measured. L-carnitine pre-incubation significantly reduced (p less than 0.001) the metabolic cardiac impairment due to doxorubicin. The inhibition of oxygen uptake declined from 38% to 7%; of ATP cellular concentration from 78% to 27%; and that of protein synthesis from 11% to 6%. L-carnitine moreover acts to eliminate completely the Ca2+ increase induced by doxorubicin. Thus, it appears L-carnitine may be useful in the prevention of doxorubicin-induced cardiac toxicity.