Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies.

BACKGROUND: SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies. PATIENTS AND METHODS: SF1126 was administered IV days 1 and 4, weekly in 28day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained. RESULTS: Forty four patients were treated at 9 dose levels (90-1110 mg/m(2)/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m(2) (diarrhoea). Exposure measured by peak concentration (C(max)) and area under the time-concentration curve (AUC(0-)(t)) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m(2). The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m(2). A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling. CONCLUSION: SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.

Effects of mitomycin C and carboplatin pretreatment on multidrug resistance-associated P-glycoprotein expression and on subsequent suppression of tumor growth by doxorubicin and paclitaxel in human metastatic breast cancer xenografted nude mice.

Overexpression of P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP), and several other proteins has been associated with development of multidrug resistance by cancer cells, which represents a significant obstacle to successful treatment by chemotherapy. We had previously demonstrated that a single noncytotoxic dose of mitomycin C (MMC), carboplatin, or one of several other DNA cross-linking agents suppressed mRNA expression of the mdr1 gene coding for Pgp, leading to a subsequent suppression of Pgp protein levels and a concomitant decrease in drug efflux. Pretreatment with MMC led to a 5- to 10-fold decrease in the ED50 for cell killing by a subsequent agent such as the Pgp substrate, doxorubicin, but did not affect killing by the non-Pgp substrate, cisplatin. In this study, we report that MMC and carboplatin each significantly suppressed Pgp protein levels in human MDA-MB-435 cells xenografted as solid tumors into the lateral mammary fat pads of female nude mice, with a similar time course as had previously been observed in cell culture. Pretreatment of mice with MMC or carboplatin 48-72 h prior to receiving either doxorubicin or paclitaxel caused a significantly greater reduction in tumor growth rate compared to either agent alone or the combination given simultaneously. These data suggest that a combination chemotherapy regimen consisting of a DNA cross-linking agent given to modulate the MDR phenotype, followed by a second cytotoxic agent, may be an effective treatment for human patients with de novo or late stage acquired multidrug-resistant malignancies.

Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable, non-small-cell lung cancer. A meta-analysis.

BACKGROUND: Survival of patients with locally advanced, unresectable (stage III), non-small-cell lung cancer treated with radiotherapy is poor. Trials of the addition of chemotherapy to radiotherapy have produced conflicting results. OBJECTIVE: To compare chemotherapy plus radiotherapy with radiotherapy alone in patients with stage III, non-small-cell lung cancer. DATA SOURCES: English-language journal articles published between 1987 and 1995 identified in a MEDLINE search. STUDY SELECTION: Randomized trials that reported survival after previously untreated patients received chemotherapy plus radiotherapy or radiotherapy alone were reviewed. DATA EXTRACTION: For all eligible articles, reported survival curves were used to determine the relative risk for death in each of 3 years. These data were combined to determine a pooled estimate of the relative risk for death at 1, 2, and 3 years. DATA SYNTHESIS: Fourteen articles reporting on a total of 2589 patients were reviewed. Compared with radiotherapy, the combination of chemotherapy and radiotherapy reduced the risk for death at 1 year (relative risk, 0.88 [95% Cl, 0.80 to 0.96]), 2 years (relative risk, 0.87 [Cl, 0.81 to 0.94]), and 3 years (relative risk, 0.83 [Cl, 0.77 to 0.90]). This corresponded to a mean gain in life expectancy of about 2 months. The magnitude of the treatment effect was similar when trials of concurrently and sequentially administered chemotherapy were considered separately. CONCLUSION: The addition of chemotherapy to radiotherapy improves survival in patients with locally advanced, unresectable, non-small-cell lung cancer. The absolute benefit is relatively small, however, and should be balanced against the increased toxicity associated with the addition of chemotherapy.

Dissociation between plasma and brain amino acid profiles and short-term food intake in the rat.

The relationship between plasma and brain amino acids and short-term food intake after administration of albumin, or its constituent amino acids, was examined. Rats given protein (0.85 g chicken egg albumin) or an amino acid mixture patterned after egg albumin reduced their food intake during 1 h of feeding beginning 30 min after gavage. Similarly, when given separately, the essential (EAA) and nonessential amino acid (NEAA) fractions of egg albumin caused comparable decreases in food intake. As the dose increased from 0.5 to 1.5 g the duration of anorexia prolonged to 12 h. Little change occurred in plasma amino acids at 30 and 60 min after albumin at 0.85 g, although many increased by 25-50% at 60 min after 1.5 g. Marked changes in plasma occurred after gavage with the total mixture of constituent free amino acids and after either EAA or NEAA fractions. Brain amino acid concentrations were little affected by albumin and did not show consistent changes after the amino acid treatments. Thus the reductions in food intake after ingestion of albumin or of its constituent amino acids were not predicted from the resulting changes in either plasma or brain concentrations of amino acids.