Despite highly toxic treatments, head and neck squamous cell carcinoma (HNSCC) have poor outcomes. There is an unmet need for more effective, less toxic therapies. Repurposing of clinically-approved drugs, with known safety profiles, may provide a time- and cost-effective approach to address this need. We have developed the AcceleraTED platform to repurpose drugs for HNSCC treatment; using in vitro assays (cell viability, clonogenic survival, apoptosis) and in vivo models (xenograft tumors in NOD/SCID/gamma mice). Screening a library of clinically-approved drugs identified the anti-malarial agent quinacrine as a candidate, which significantly reduced viability in a concentration dependent manner in five HNSCC cell lines (IC50 0.63–1.85 μM) and in six primary HNSCC samples (IC50 ~2 μM). Decreased clonogenic survival, increased apoptosis and accumulation of LC3-II (indicating altered autophagy) were also observed. Effects were additional to those resulting from standard treatments (cisplatin +/– irradiation) alone. In vivo , daily treatment with 100 mg/kg oral quinacrine plus cisplatin significantly inhibited tumor outgrowth, extending median time to reach maximum tumor volume from 20 to 32 days ( p < 0.0001) versus control, and from 28 to 32 days versus 2 mg/kg cisplatin alone. Importantly, combination therapy enabled the dose of cisplatin to be halved to 1 mg/kg, whilst maintaining the same impairment of tumor growth. Treatment was well tolerated; murine plasma levels reached a steady concentration of 0.5 μg/mL, comparable to levels achievable and tolerated in humans. Consequently, due to its favorable toxicity profile and proven safety, quinacrine may be particularly useful in reducing cisplatin dose, especially in frail and older patients; warranting a clinical trial.

Febrile neutropenia in patients who have undergone chemotherapy is usually treated with a combination of broad-spectrum antibiotics. There are no exactly defined protocols for single-agent treatment because a clear definition of low risk febrile neutropenia is lacking. This paper examines the safety and efficacy of once-daily ceftriaxone in 376 cases. Material and Methods: In a prospective observational study carried out between February 1992 and January 1996, 959 febrile episodes at 48 hospitals were recorded. Inclusion criteria were neutropenia (absolute neutrophil count, ANC <1,000/µl) with fever (≥38.5°C) or a C-reactive protein concentration >1 mg/dl and suspected infection. Nine hundred and one episodes (acute leukemia n = 396, lymphoma n = 220, solid tumors n = 272 and other disorders n = 13) in 828 patients aged between 1 and 97 years were analyzed, of which 876 episodes were evaluable for response. All patients initially underwent empirical treatment with ceftriaxone (adults: 2 g/day; children: 80 mg/kg/day), either alone (376) or in combination with other agents (525). Results: The mean ANC was 423/µl (SD ± 316) and the median duration of neutropenia 10 days. Of the 363 episodes treated initially with ceftriaxone alone, 70.8% responded versus 56.9% in the combination therapy group. The favorable response to the initial monotherapy treatment was explained by a low-risk population in the monotherapy group. A KI >6 (p < 0.0001), ANC ≥500/µl (p = 0.0001) and a duration of ANC <5 days (p < 0.05) were significantly more frequent in the monotherapy arm and were predictive of lower risk at the commencement of treatment. Conclusion: Ceftriaxone is effective in febrile neutropenia. Treatment with ceftriaxone alone was safe and highly effective in low-risk patients. Single-agent regimens appear to be a suitable treatment option in low-risk febrile neutropenia.

Summary:Mobilised peripheral blood stem cells are widely used for autografting in patients with chronic myeloid leukaemia (CML) and it is generally thought that a high proportion of Ph-negative progenitor cells in the graft is desirable. We report here the results of 91 stem cell mobilisations performed with various chemotherapy regimens followed by G-CSF. We show that mobilisation of Ph-negative cells is possible after diagnosis as well as in advanced stages of the disease. The yield of Ph-negative cells is highly dependent on the chemotherapy regimen: while the combination of idarubicin and cytarabin for 3-5 days (IC3-5) mobilised Ph-negative cells in most patients, high-dose cyclophosphamide was ineffective. Mobilisation of Ph-negative progenitor cells after IC3 was at least as effective as after IC5; however, less apheresis sessions were required, and toxicity was much reduced after IC3. Compared to historical controls, IC was equally effective as the widely used ICE/minilCE (idarubicin, cytarabin, etoposide) protocol. No correlation was found between graft quality and the cytogenetic response to subsequent treatment with interferon-␣. We conclude that IC3 is an effective and well-tolerated regimen for mobilising Ph-negative cells that compares well with more aggressive approaches such as IC5 and ICE/minilCE. Bone Marrow Transplantation (2001) 27, 1125-1132.

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