C. Rosenfeld

Two epipodophyllotoxin derivatives, VM 26 and VP 16213, in the treatment of leukemias, hematosarcomas, and lymphomas

The preliminary results obtained with VM 26 and VP 16213 (two semisynthetic derivatives from epipodophyllotoxin) on leukemias and hematosarcomas are described. These compounds are phase M dependent, myelostatic agents whose toxicity can be controlled by intermittent administration. VM 26 proved capable of inducing regression in Hodgkins disease, reticulosarcomas, and lymphosarcomas. Its most remarkable effect was the total regression of neoplastic pleural effusions by systemic administration. VP 16213 seemed to be effective on the same hematosarcomas, but less often. Its most striking action was its oncostatic effect in acute monocytoid leukemia and in the monocytoid component of acute myelomonocytoid leukemia.

Hydroxyurea, Leucopheresis, and Splenectomy in Chronic Myeloid Leukaemia at the Problastic Phase

Forty-three patients with chronic myeloid leukaemia have been treated with hydroxyurea in order to be subjected to leucopheresis for white cell transfusions. Hydroxyurea decreases leucocytosis when it is administered and the blood granulocyte number increases soon after the drug is stopped. The survival of the patients is not different from the survival of the patients treated with conventional chemotherapy (busulphan, mitobronitol) and it is superior to the survival of patients treated with external radiotherapy or with 32P. Half of the patients were subjected to splenectomy during first remission for a phase II trial. They were not randomized, but the distribution according to age was similar in the two groups. A slight difference appears in favour of splenectomy so far as survival is concerned, but there were three post-operative deaths out of 18 patients. We conclude that a phase II trial on the value of splenectomy is indicated ethically, but that the patients should be operated on and nursed in a microbiologically controlled environment.

Pathogen-free isolation unit — Three years' experience

The results obtained during the first three years of a pathogen-free isolation unit containing five beds have shown that this type of unit can reduce the risk of infection in patients treated with intensive chemotherapy or in those who have granulocytopenia from various causes. It is suggested that treatment of cancer which involves these risks should be carried out routinely in sterile isolation units, and that it is urgent to build many more and much larger units.

Dynamic and Composition of Cellular Membranes and Serum Lipids in Malignant Disorders

The dynamic structural organization of the surface membrane in mammalian cells is now widely accepted and in some cases even well-documented. However, the general term “membrane fluidity” commonly employed in this respect is actually complex and covers different properties of the membrane. The most prominent of these are: (a) the degree of lateral and rotational mobilities of membrane protein receptors [9,22] and (b) the degree of viscosity of the surface membrane lipid core [6, 7, 10, 20]. These dynamic features of the cell surface membrane, which to some extent are interrelated [21], are now believed to play a major role in cellular control mechanisms that determine normal and abnormal cell growth and differentiation [2, 3, 8, 11, 15]. Moreover, since by definition, all membrane protein receptors are embedded to some extent in the membrane lipid core, the dynamic nature or the lipid domain that is determined by its lipid composition may determine to a large extent functional activities of proteins that are embedded in it.

Attempts at Immunotherapy of 100 Acute Lymphoid Leukemia Patients: Some Factors Influencing Results

There is an extensive literature on experimental active immunoprevention of cancer, which is the stimulation of immune reactions before the establishment of the tumor. This stimulation can be specific, consisting of the administration of irradiated neo-plastic cells, which generally produces a moderate effect [10, 22] or it can be nonspecific, consisting of the application of one or several agents that we have called “systemic immunity adjuvants” (SIA) [13], the most widely used being BCG injected intravenously [2, 4, 21, 26]. A marked effect is generally achieved by a combination of both means. Though the agents are administered by different routes, the effect of combined administration is usually much greater than that of the adjuvant given alone, which is itself superior to that of the irradiated tumor cells (ITC) [21].

Adriamycin in the Treatment of Acute Leukemias

This paper describes the results of our clinical trial of adriamycin in the treatment of acute leukemias, done after the first results of Bonadonna et al. [1]. A trial of this drug in solid tumors is at present being made by the “clinical screening group” of the European Organisation for Research on the Treatment of cancer (E.O.R.T.C.).

REMISSION INDUCTION WITH POLY IC IN PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA (PRELIMINARY RESULTS)

The oncostatic effect of polyinosinic-polycytidylic acid (poly IC) on several varieties of tumors has been reported previously (Levy et al., 1969) and we have observed its effect on Walker’s tumor. A number of clinical trials have been conducted (De Vita et al., 1970; Krakoff et al., 1970) but they merely confirmed tolerance to the product and did not yield therapeutical results. Although the mechanism of the oncostatic action exerted by polynucleotides on experimental tumors is not precisely defined, it is thought that it is probably multiple, for poly IC is cytotoxic (Braun, personal communication), is an inducer of interferon (Field et al., 1967), is an adjuvant of immunity, as reported by Braun et al. (1968), and as observed by us by studying its effect on the multiplication of cells capable of forming antibodies in mice immunized with sheep red blood cells (Hayat and Mathe, in preparation). From this last-mentioned type of study, we have deduced the hypothesis according to which poly IC could have an action on acute leukemia only when the number of tumor cells is not very high. In fact, we have shown (Mathe, 1968; Mathe et al., 1969) that the adjuvants of immunity in the animal exert a detectable oncostatic action only when the number of cancer cells is low.

Preliminary Data on Acute Leukemia Treatment with ICRF 159

We have treated 10 patients with acute leukaemia, 7 lymphoblastic and 3 myeloblastic, with ICRF 159 or dioxopiperazine propane (Fig. 1). All these patients were resistant to all the drugs so far available. The daily doses were 300 mg/m2.

Five Years Experience of the Clinical Use of a Pathogen-Free Isolation Unit

Intensive chemotherapy and radiotherapy in current use in the treatment of malignant disease have given some outstanding results (Mathe et al., 1968) but they can cause, virtually inevitably, periods of profound hypo- or aplasia of the haemopoietic and lymphopoietic systems, whose main complication is infection. Infection has become one of the principal problems in the practice of modern cancer therapy, being particularly formidable in malignant disease of the haemopoietic system, especially in leukaemiC., where bone marrow insufficiency is often present before giving any treatment. In a recent study of acute leukaemia, treated with intensive chemotherapy, Frei and his colleagues (1965) reported 60 per cent incidents of bacterial infection with 40 per cent of septicaemia, and 64 per cent incidents of fungal infections with 34 per cent of septicaemia. Autopsy examination has confirmed that infection is the commonest direct cause of death in these cases.

Comparative Results Obtained in the Treatment of Acute Lymphoid Leukemia, Acute Myeloid Leukemia, and Acute Monocytoid Leukemia

Acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) patients have been treated in our Institute according to different therapeutic principles (Fig. 1). In ALL we have tried to induce remission with chemotherapy, then applied complementary cell-reducing systemic chemotherapy combined with CNS chemoradiotherapy in order to reduce by three or four orders of magnitude the number of leukemic cells left by induction chemotherapy; finally we have submitted the patients to active immunotherapy, which is a combination of the injection of allogeneic leukemic cells and the administration of systemic adjuvants of immunity such as BCG [1, 2].