We have studied the influence of interferons (IFNs) on the metastatic potential of mouse colon adenocarcinoma, COLON 26, cells. Pre-treatment of the cells in vitro for 24 hr with recombinant murine IFN-gamma (rMuIFN-gamma) significantly increased the number of lung tumour nodules when cells were injected i.v. into immunocompetent BALB/c mice and BALB/c nude mice. However, when MuIFN-gamma-pre-treated cells were injected into beige (NK-deficient) nude mice or anti-asialoGM 1 (asGM 1)-serum-treated BALB/c mice (NK-depleted) no enhancement of metastatic potential was seen. Pre-treatment of COLON 26 cells with recombinant human IFN-alpha A/D (Bg1 I), an IFN with equal activity on human and mouse cells, did not significantly enhance their subsequent metastases in immunocompetent or immunodeficient mice. In fact, there was a small but significant decrease in the number of tumour nodules in the lungs of beige nude and asGM 1-treated mice. The effects of rMuIFN-gamma on COLON 26 cells did not appear to be related to an alteration in MHC expression. COLON 26 cells constitutively express H-2D and H-2K antigens and both IFNs had equal enhancing (approx. 2-fold) activity on the expression of these antigens at the doses used in this experiment (10(3)U/ml). We conclude that pre-treatment with rMuIFN-gamma renders COLON 26 cells resistant to in vivo NK-cell lysis via a mechanism that does not involve changes in MHC expression.

A recombinant human hybrid alpha interferon (rIFN-alpha A/D) with antiviral, immunomodulating and cell-growth-inhibitory activity on murine cells strongly inhibited the development of experimental pulmonary metastases of the Colo 26 adenocarcinoma in BALB/c mice. Twenty-one days after i.v. injection of 5 X 10(4) cells, 8/8 control mice had greater than 200 lung tumour nodules whereas 1/6 mice receiving 500 ng rIFN-alpha A/D had one lung tumour nodule and the other 5 mice were tumour-free. Equally strong inhibition was seen in immunodeficient BALB/c nu/nu (athymic) and beige nu/nu (athymic and NK-deficient) mice. Scheduling experiments in vivo showed that the most important time of IFN treatment was from the day of tumour cell injection to day 5, although statistically significant reductions in lung tumour nodule number and lung weight were seen even when IFN treatment was started 7 days after cell injection. rIFN-alpha A/D was cytostatic to Colo 26 in vitro, causing 50% or more inhibition of cell growth or colony number at IFN levels that could be achieved in the sera of IFN-treated mice. Although rIFN-alpha A/D stimulated NK-cell activity in BALB/c mice, Colo 26 cells were resistant in vitro to such cells whether from control or IFN treated mice.

This report describes a case of fatal haemolytic uraemic syndrome (HUS) developing in a child with acute lymphoblastic leukaemia (ALL) during induction chemotherapy. The aetiology in this case is uncertain but it may have resulted from treatment with L-asparaginase or vincristine. The possibility of HUS during induction chemotherapy for ALL should be considered early on in the treatment regimen, if clinical signs and symptoms suggest this diagnosis, so that appropriate treatment can be instituted. W e report a fatal case of haemolytic uraemic syndrome (HUS) developing in a child with acute lymphoblastic leukaemia (ALL) during induction chemotherapy. The aetiology was uncertain but treatment with L-asparaginase or vincristine might be involved. The possibility of HUS during induction chemotherapy for ALL should be considered early on, if clinical signs and symptoms suggest this diagnosis, so that appropriate treatment can be instituted. CASE REPORTA four year old girl presented with a five day history of lethargy and bruising. A diagnosis of common acute lymphoblastic leukaemia (ALL) was made after appropriate investigations. The patient was started on induction chemotherapy according to schedule A of the Medical Research Council UK ALL 97/01 protocol. She received dexamethasone 6.5 mg/m 2 /day, vincristine 1.5 mg/m 2 /week, and L-asparaginase (Escherichia coli) (Elspar; Merck, West Point, USA) 6000 units/m 2 on alternate days. She was discharged eight days after diagnosis with further treatment on an outpatient basis.She was readmitted 10 days after her first admission (day 16 of chemotherapy), with fever, neutropenia, and cellulitis over the left gluteal region.She was treated with oxygen, intravenous fluids, meropenem, gentamicin, flucloxacillin, and fluconazole and continued to receive induction chemotherapy.The initial blood culture grew E coli, which was not the O157 strain and was negative for verocytotoxin. It was sensitive to meropenem, gentamicin, and ceftazidime. The patient's fever subsided within 24 hours of starting antibiotics.Four days (day 20 of chemotherapy) after readmission the patient developed deranged renal function with declining urine output. Biochemical investigations (previously normal) showed a rising blood urea and serum creatinine. An abdominal ultrasound revealed an increase in size and echogenicity of both kidneys. She also had an increased blood and platelet requirement and had poor platelet increments after transfusions. Figure 1 shows the results of the haematological and biochemical investigations.A possibility of drug induced interstitial nephritis resulting in acute renal failure was considered and meropenem and gentamicin were replaced with ceftazidime. Her fluid intake was restricted to 400 ml/m 2 /day and she was investigated for platelet refractoriness.Over the next two days, the patient became increasingly drowsy (Glasgow coma scale (GCS) 13/15) and her renal function and urine output deteriorated further. Investigations revealed raised lactate dehydrogenase (6353 IU/ li...

The therapeutic potential of rHuIFN-alpha A/D, a hybrid human IFN molecule with equal activity on murine cells, was studied in experimental and spontaneous metastatic models of a murine colon carcinoma COLON 26. rHuIFN-alpha A/D inhibited experimental pulmonary metastases of COLON 26 and prolonged the survival of BALB/c mice. Dose scheduling, survival and tumour-cell clearance studies showed that the first 5 days were critical in the inhibition of pulmonary metastases. However, it is unlikely that lung NK cells were involved in the anti-metastatic effect of rHuIFN-alpha A/D because inhibition of pulmonary metastases and a decrease in radio-labelled tumour-cell survival was seen in BALB/c mice depleted selectively of their NK cells by prior treatment with rabbit antiasialoGMI serum. Although rHuIFN-alpha A/D stimulated NK-cell activity in BALB/c mice, it was ineffective in abrogating the NK suppressant action of rabbit anti-asialoGMI serum on murine lung NK cells. Thus, IFN may mediate its early antimetastatic effect via a mechanism independent of NK-cell stimulation. IFN also inhibited the development of lung metastases from s.c. COLON 26 tumors in normal, NK-depleted and T-cell-deficient mice.

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