Primary hypothyroidism associated with interferon therapy of breast cancer.
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Adult↗
Biomedical subjects
F R Balkwill
Publications and source records attributed to F R Balkwill.
Differential action of six human interferons against two human carcinomas growing in nude mice.
Six different pure human interferons (IFNs), were tested for anti-tumour effect against two human carcinomas, breast and bowel, growing in nude mice, in a total of 36 experiments. The IFN-alpha mixture, analogue and subtypes showed the greatest activity, particularly against the breast cancer xenograft, whereas IFN-beta and IFN-gamma had little effect. However, circulating IFN could be found in the sera of mice treated with all 3 IFN types. In terms of amount of IFN protein, IFN-alpha Con1, an IFN-alpha analogue, was the most effective, a dose of 0.1 micrograms/mouse/day being sufficient to induce breast tumour regression, and IFN-gamma the least effective, a dose of 10 micrograms/mouse/day having no effect on the same tumour. A more detailed comparison of 2 IFN-alpha subtypes showed that a daily dose of 1 microgram IFN-alpha A was more effective than the same dose of IFN-alpha D, but as this IFN had approximately 30 times less antiviral activity on human cells than IFN-alpha D, these IFNs were probably at least equally effective in terms of human cell units. IFN-alpha D stimulated mouse spleen natural killer cell activity but it was not clear whether this stimulation was involved in anti-tumour activity. We conclude that this model system is useful for investigating direct anti-tumour activity of a wide range of IFN types and subtypes.
2',5'-Oligoadenylate Synthetase↗
Recombinant DNA human interferon alpha 2 in advanced breast cancer: a phase 2 trial.
Effectiveness of recombinant DNA (rDNA) human interferon alpha 2 (IFN alpha 2) in advanced breast cancer was evaluated in 14 patients who had received prior endocrine and/or cytotoxic therapy. After randomization, 7 patients received IFN alpha 2 two million IU m-2 day-1, s.c., 3 times a week (schedule 1) and 7 patients received 50 million IU m-2 day-1, i.v., for 5 consecutive days, every 3 weeks (schedule 2). Treatment duration was 4-21 weeks in schedule 1 and 6-24 weeks (2-8 courses) in schedule 2. Regressions were not achieved with either schedule. Treatment was associated with significant toxicity and was more severe in schedule 2. Dose limiting toxicities were leukopenia, elevation of liver enzymes, hyperglycemia and fatigue. Serum IFN activity was low or undetectable in patients on schedule 1 and high in patients on schedule 2. At 24 h, serum IFN activity was detectable in only 1/6 patients on schedule 1 as compared to 3/7 patients on schedule 2. IFN neutralizing factors were detected in the serum of only 1 patient prior to treatment but none were detected in any of the patients during or after discontinuation of treatment (4-24 weeks). IFN alpha 2 increased the expression of both HLA class 1 antigens and beta 2 microglobulin in peripheral blood lymphocytes in vivo. This effect was dose related.
Adult↗
Preclinical and clinical studies of interferons and interferon inducers in breast cancer.
Preclinical and clinical studies suggest interferons and interferon inducers have antitumor activity for breast carcinoma. Observations include inhibition of growth of freshly derived and continuously passaged breast carcinoma cells in vitro, decreased tumor size and increased survival in spontaneous mouse mammary carcinoma, inhibition of growth of xenogeneic human breast carcinomas grown in nude mice, and reduction of measurable tumors in women. Since clinical doses and schedules have to date been largely empirically derived, additional studies will be required to define optimal clinical use. Furthermore, not all interferon types or subtypes may prove clinically effective. Therefore, use of interferons or interferon inducers in patients should remain restricted to controlled trials with well-defined research objectives.
Adult↗
Differential effects of pure human alpha and gamma interferons on fibroblast cell growth and the cell cycle.
Pure human alpha and recombinant gamma interferons had differential effects on two strains of fetal lung fibroblasts in vitro. Alpha interferon had little effect on long-term cell growth, whereas gamma interferons, both glycosylated and non-glycosylated, were cytotoxic. However, when synchronized cells were studied, alpha interferon prolonged both G1 and S + G2 phases of the cell cycle, whereas gamma interferon only affected the G1 phase.
Cell Cycle↗
Positive interactions between interferon and chemotherapy due to direct tumor action rather than effects on host drug-metabolizing enzymes.
The mechanism of increased antitumor activity when human lymphoblastoid interferon [HuIFN-alpha(Ly)] and the drugs cyclophosphamide and Adriamycin are used in combination on a human tumor xenograft in nude mice has been investigated. HuIFN-alpha(Ly) did not affect hepatic levels of the drug-metabolizing enzymes cytochrome P-450 or the glutathione S-transferases. In contrast, mouse interferon caused significant and differential changes in the isozymic forms of these enzymes. However, addition of mouse interferon to the HuIFN-alpha(Ly)/cyclophosphamide or Adriamycin combinations had no effect on the final result, and did not increase the toxicity of the combination therapy. These data provide evidence that the increased activity of the combination therapy is due to effects on the tumor rather than on the host. Further studies showed significant perturbations in the tumor cell cycle after in vivo combination therapy. Cyclophosphamide caused an accumulation in G2 and the addition of HuIFN-alpha(Ly), which alone caused little change in cycle distribution, delayed this G2 block and strongly increased the number of cells in S phase. A similar, although less pronounced, effect was seen with HuIFN-alpha(Ly)/Adriamycin therapy. The increase in S phase seen in combined therapy may account for the synergy seen.
Adenocarcinoma, Mucinous↗
Positive interactions between human interferon and cyclophosphamide or adriamycin in a human tumor model system.
Human lymphoblastoid interferon strongly increased the anti-tumor activity of suboptimal doses of two commonly used anti-cancer drugs, cyclophosphamide and Adriamycin, on a human breast tumor xenograft growing in nude mice. A combination of human lymphoblastoid interferon with either of these agents caused regression and in some cases total disappearance of tumors at doses of drug and interferon that, used singly, were capable only of inhibiting tumor growth. The combined therapy also resulted in a greatly increased survival. Studies with interferon and cyclophosphamide indicated that the antitumor activity was greatest when the two agents were administered simultaneously rather than sequentially.
Animals↗
Immune human lymphocytes produce an acid-labile alpha-interferon.
We have described in this paper a novel human interferon (IFN) with antigenic and cross-species reactivity of alpha-IFN and physicochemical properties of gamma-IFN. This IFN is produced by normal peripheral blood mononuclear cells during an immune response but has also been associated with autoimmune disease (10). The system described here will be useful in elucidating the biological significance and cell of origin of this IFN.
Animals↗
Experience with human lymphoblastoid interferon in acute myelogenous leukaemia (AML).
Fourteen patients with acute myelogenous leukaemia, who had either failed to enter remission or had relapsed following conventional chemotherapy, received human lymphoblastoid interferon (Hu IFN-alpha N) at a dose of 100 X 10(6) units/m2 daily by continuous IV infusion for 7 days. Complete remission was not achieved in any of 10 patients evaluable for response, although a transient decrease in the degree of bone marrow infiltration was observed in two patients.
Adult↗
Central nervous system toxicity of interferon.
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Central Nervous System Diseases↗
Implications for clinical application of new developments in interferon research.
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Animals↗
Human interferon inhibits the growth of established human breast tumours in the nude mouse.
In this paper we describe a model system for looking at the effects of human interferon, IFN, on an established human tumour. Highly purified human IFN derived from lymphoblastoid cells (HuIFN alpha-Namalwa) strongly inhibited the growth of a human breast cancer growing as a xenograft in nude mice. The effect was dose-dependent, required daily treatment for an optimal effect and was time-dependent, little inhibition being seen before 2 weeks of therapy. With the doses used, however, neither tumour regression nor disappearance were seen and on morphological examination, treated tumours appeared as miniatures of control tumours. The inhibition of the tumour by HuIFN alpha-Namalwa appeared to be due to a direct effect on the human cells as this IFN had little effect on the mouse immune system in vitro as measured by NK cells activity. Also HuIFN therapy had no effect on levels of an interferon induced enzyme, 2-5A synthetase, in the mouse spleen cells but stimulated this enzyme in the human tumour.
2',5'-Oligoadenylate Synthetase↗
A phase I study of human lymphoblastoid interferon administered by continuous intravenous infusion.
A phase I study of human lymphoblastoid interferon (IFN-alpha) was undertaken in patients with acute leukaemia and other malignancies. The pharmacokinetics of intravenous IFN-alpha were also investigated. IFN-alpha was administered to two patients by intravenous (IV) bolus injection at a dose of 5 X 10(6) U/m2; and to a further 37 patients (40 cycles) by continuous intravenous infusion (IVI) for 5, 7, or 10 days at doses ranging from 5 to 200 X 10(6) U/m2/day. Pyrexia, general malaise, anorexia, and rigors were observed at all dose levels; three patients became hypotensive. Myelosuppression occurred in all patients, including seven without bone marrow infiltration. Transient rises in alkaline phosphatase and transaminases (SGOT) were observed in patients receiving daily doses greater than 30 X 10(6) U/m2. Dose-limiting central nervous system toxicity, hyperkalaemia, and hypocalcaemia were encountered at 200 X 10(6) U/m2. In six patients with acute leukaemia there was a fall in the number of circulating leukaemic blasts and in one patient with acute myelogenous leukaemia (AML) the degree of bone marrow infiltration decreased from 99% to less than 5% with cellularity returning to normal. Serum levels of IFN above 1,000 U/ml were achieved with daily doses above 30 X 10(6) U/m2 given by IVI. The maximum safely tolerated daily dose, 100 X 10(6) U/m2 administered for 7 days, is appreciably higher than that used in most previous studies, although even at this level considerable toxicity may be encountered.
Blood Cell Count↗
Effects of HuIFN-alpha 2 and HuIFN-alpha (Namalwa) on breast cancer cells grown in culture and as xenografts in the nude mouse.
The activity of HuIFN-alpha 2 produced in bacteria has been compared with that of HuIFN-alpha from Namalwa cells (HuIFN-alpha N) as an antiviral (against EMC virus) and antiproliferative agent in normal and malignant cultured human breast cells. The IFN preparations show the same spectrum of antiviral and antiproliferative activity in the human cell strains and lines examined, and are equally effective, when comparable amounts of IFN protein are used. Both interferon preparations inhibit virus growth (EMC) in four types of bovine cells but neither inhibit the growth of these cells. HuIFN-alpha 2 and HuIFN-alpha N can also be shown to effectively inhibit the growth of a transplantable human breast cancer, grown as xenografts in the nude mouse, although the amounts of IFN protein required may not be the same for both preparations.
Animals↗
The ppp(A2'p)nA and protein kinase systems in wild-type and interferon-resistant Daudi cells.
Daudi cells, a human lymphoblastoid line, are exceptionally sensitive to the growth inhibitory effects of interferon, 1 unit/ml being sufficient to inhibit cell growth. In addition, interferon treatment of these cells severely inhibits the incorporation of exogenous thymidine into DNA and causes cells to accumulate in the G1(G0) at the expense of the S phase of the cell cycle. The possible involvement of ppp(A2'p)nA(n = 2 to less than or equal to 4) in these effects has been investigated. No (less than 1 nM) ppp(A2'p)nA or (A2'p)nA or alternative products of the ppp(A2'p)nA synthetase [e.g. NAD (2'pA)2] were detected in interferon-treated cells. In addition no evidence was obtained for the occurrence of ppp(A2'p)nA-mediated ribosomal RNA cleavage in these cells even after several days of treatment with relatively high doses of interferon. A line of Daudi cells which is resistant to all three of the above effects of interferon was selected. The wild type and resistant lines were compared with respect to the ppp(A2'p)nA and interferon and double-stranded RNA (dsRNA)-mediated protein kinase systems. The resistant line was not receptor-negative as it responded to interferon by the production of elevated levels of the ppp(A2'p)nA synthetase similar to those observed in extracts from wild-type cells. There was no detectable difference between the lines in the levels of the (2'-5')phosphodiesterase responsible for the degradation of ppp(A2'p)nA. There was, however, about a twofold increase in the ppp(A2'p)nA-dependent endoribonuclease activity in response to interferon with extracts from the wild-type but not the resistant cells. In addition, although the dsRNA-dependent protein kinase activity increased in both types of cell there was a striking reduction in the level of protein phosphorylation in general in response to interferon with material from the wild-type but not the resistant cells.
2',5'-Oligoadenylate Synthetase↗
Species restriction in cytostatic activity of human and murine monocytes and macrophages.
The pattern of species restriction in cytostatic activity of human breast-milk macrophages (Mph) and murine starch-activated peritoneal exudate (PE) Mph was investigated. Human Mph had appreciable cytostatic activity only for human target cells and not for murine or avian target cells. In contrast, murine Mph were particularly cytostatic for target cells from heterologous species and not as cytostatic for other murine cells. This difference in the activity of murine Mph was more notable when freshly explanted fibroblasts were used as target cells than when the cytostasis of long-term tissue culture lines was measured. Experiments with peripheral blood monocytes from the two species indicated that this pattern of reactivity may be common to mononuclear phagocytes from other sources. Therefore, human Mph are preferentially cytostatic for target cells of self species; whereas, murine Mph are equally if not more cytostatic for target cells from other species.
Animals↗
Remission in acute myeloblastic leukaemia.
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Cell Differentiation↗
Characterization of human breast milk macrophages cytostatic for human cell lines.
Approximately 40% of the cells in human early lactation milk possessed the characteristics of macrophages, being adherent, phagocytic, alpha napthyl acetate esterase positive, and possessing C3b and Fc receptors. These cells were also cytostatic for MDA 157, a cell line derived from a pleural effusion of human breast cancer, and HEL 23, a strain of human fetal lung fibroblasts. Investigations into the cytostatic phenomenon indicated that the cytostasis could not be mediated by macrophage-conditioned medium and that very close contact between breast milk macrophages and target cells was required. Cytostasis was not fully effective until 18 hr after the initial interaction between macrophages and target cells.
Breast↗