S-y AQ4N (l,4-bLs-q25ddimthyai oo y}amin5dydroxy-anthrane-9,10-dione) is a novel alkylaminoanthraquinone N-oxide which, on reducin, forms a stable DNA affinic cytotoxi compound AQ4. The The failure to cure tumours with radiotherapy and chemotherapy has been attributed in part to the presence of treatment-resistant subpopulations of hypoxic tumour cells (Bush et at., 1978). Bioreductive agents provide a novel approach to this problem: reduction of the prodrug within a hypoxic cell to produce a cytotoxic metabolite should selectively target this sub population within tumours. Since normal tissus contain few, if any, poorly oxygenated cells, systemic reductive activation and its attendant toxicity should be minimal. Several classe of bioreductive agents have been described, icluding the nitroimidazoles, benzotriazene di-N-oXides and mitosenes (Workman, 1992). Using a different class of compounds, i.e. the anthraquinones, we have developed a novel alkylamnoanthraquinone N-oxide, AQ4N (1,4-bis-{[2-(di-methylamino-N-oxide)ethylarmino}5,8-dihydroxyanthracene-9,10-ione), which is susceptible to reduction under hypoxic conditions (Patterson, 1993). AQ4N is a weak DNA-binding agent and weak topoisomerase H inhibitor, critically, the electrically neutral N-oxide function prevents stable binding to the DNA helix (Patterson, 1993). In contrast, the reduction product of AQ4N, i.e. AQ4 (1,4-bis-{[2-(dimethylamino) ethylnamino}5,8-dihydroxyanthracene-9,10-dione) (Figure 1), is a cationic compound with high affinity for DNA. Interaction of AQ4 with DNA is facilitated by the planar, eletrondeficient antraquinone chromophore intercalating between adjcent DNA bases. Tlis complex is further stabiised by electrostatic interactions and hydrogen bonding with the deoxyribose phosphate backbone, as has been observed for similar anthraquinones (Denny and Wakelin, 1990 al., 1992). This will allow metabolism of the drug in cells which will contribute, when the hypoxic stimulus is removed, to the main growth frction within the tumour. Secondly, the drug can be combined with an agent which is selectively toxic to well-oxygenated cells to evahuate the effect of targeting the two subpopulations of cells (Brown and Lemmon, 1991;Grau and Overgaard, 1991). We have used both these approaches to study the effect of AQ4N on tumour growth in vivo. Firstly, we tested the anti-tumour effect of AQ4N when combined with hypobaric hypoxia. Following this we combined AQ4N with radiation as both single and fractionated doses. Materiak an mth Tumour systemThe T50/80 tumour is a poorly differentiated mammary carcinoma which arose in a B6D2FI mouse. Tumour and breeding colonies for mice were obtained from Dr JV Moore, Paterson Laboratory, Christie Hospital, Manchster, UK.Male B6D2FI mice aged 8-12 weeks were used for all studies, which were carried out in accordance with the UK. Animals (Scientific Procedures) Act 1986. The tumour has been maintained by intadermal passage for up to ten passages and then re-establshed from frozm stock. Tumour brei (0.05 ml) w...

Anal tumours represent 5 per cent of anorectal cancers and exist as two clinical entities: tumours of the anal canal and those of the anal margin. Smoking and sexual behaviour, particularly homosexual anal intercourse, are important aetiological factors. This association is related to anal warts and human papillomavirus infection, notably type 16, which is found in around 70 per cent of warts. Symptoms are non-specific and are frequently attributed to benign conditions. Rectal examination reveals a characteristically infiltrating lesion and any suspicious anal area should be biopsied. There are two histological types. Squamous carcinoma comprises approximately 95 per cent of anal tumours and includes the 35 per cent of tumours derived from the anal transition zone (cloacogenic tumours), containing a mixture of squamous and mucinous elements. The remaining 5 per cent of anal tumours are adenocarcinoma. Squamous cell tumours of the anal canal are probably best treated using radiotherapy (with chemotherapy) as complete response rates, 5-year survival rates, and incidences of normal sphincter function and significant toxicity are around 80, 70, 75 and 20 per cent respectively. Treatment failures may be salvaged by surgery. The 5-year survival and local recurrence rates for radical surgery are around 60 and 25 per cent respectively; there are few indications for local excision. In contrast, 60 per cent of anal margin tumours are suitable for local excision, the 5-year survival rate being in excess of 80 per cent. Combining radiotherapy with surgery may give additional benefit. Current randomized controlled trials should further clarify the relative merits and demerits of the treatment options.

No clinically relevant differences in the pharmacokinetics of capecitabine and its key metabolites 5'-DFUR, 5'-DFCR, and 5-FU were found between Japanese and Caucasian patients. Plasma concentrations of FBAL were higher in Caucasian than in Japanese patients but this difference is not clinically relevant as FBAL has no antiproliferative activity and systemic exposure to FBAL does not correlate with the tolerability of capecitabine.

No abstract

Summary Recombinant human erythropoietin (rHuEpo) has recently become available for the treatment of chronic anaemia, including that associated with cancer. Carcinoma NT in CBA mice causes a progressive anaemia which can be overcome by daily injections of recombinant human erythropoietin (rHuEpo). This model was used to study the effect of haematocrit on tumour blood flow, growth rate and radiosensitivity, in mice with haematocrits ranging from approximately 38% (control) to 65% (20 U/day rHuEpo). Tumours showed a small but significant slowing in growth rate with higher haematocrit. In vitro studies showed rHuEpo had no direct effect on the growth of NT cells. Tumour blood flow was measured by two methods in each mouse ('33Xe clearance and 86Rubidium uptake). Blood flow showed a tendency to decrease with increasing blood viscosity although this effect was not significant despite the large differences in haematocrit. Although tumour doubling time was prolonged despite the large differences in haematocrit. Although tumour doubling time was prolonged with increasing radiation dose, from 0 (sham irradiated) tq 35 Gy, haematocrit was not found to influence the growth delay. This was attributed to adaptation of the tumour during the relatively slow change in the haematocrit. rHuEpo is being considered for clinical use in anaemic cancer patients. Our data suggest that this treatment will correct haematocrit with no effect on tumour radiosensitivity.