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Three phase I/II trials were performed in patients with metastatic colorectal cancer using immunochemotherapy--a combination of recombinant interferon beta and gamma with low doses of cytostatic drugs. The third regimen, consisting of a cytostatic component containing 5-fluorouracil plus carboplatin plus mitomycin C besides the interferons, produced a high remission rate of 47%: 14/30 patients responded. The tolerability of this protocol was good and it could be administered on an out-patient basis.

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Low doses of cyclophosphamide (CPA) modulate immune responses and induce complete tumor regression and cures in mice. The mechanism of action is related to the development of a T-cell-dependent immune reaction. We started a trial with mafosfamide (MAF), the active metabolite of CPA and found that the response of Ehrlich ascites-tumor (EAT) cells in vivo to this compound is biphasic. The highest cure rate (70%) is obtained with a low i.p. dose of 7 mg/kg/d. Hematologic side effects were not observed. Arguments for an immune mechanism involved are that (1) mice treated with MAF showed a statistically significant increase in spleen weight compared with untreated controls, (2) after treatment large numbers of mononuclear cells appeared in the ascites, and (3) long-term surviving mice were resistant to further challenge with large inocula of EAT. We started a pilot trial in patients with metastasizing and advanced renal cell carcinoma - a disease which can be considered to be influenced by the immunologic response of the tumor host. The starting dose of MAF was 24 mg/m2/d administered i.v. Therapy was repeated at 14 days interval on an out-patient basis. Monitoring of mononuclear cells in the peripheral blood with monoclonal antibodies using a FACS IV were performed two times a week. There are eleven patients on study. Up to now, four out of them have been fully evaluated with respect to toxicity, immune modulation and tumor response. With respect to response to treatment, 2 patients had no change of disease, 1 patient had a mixed and 1 patient a partial response. No hematological or other toxicities could be observed. All patients showed an increase in monocytes/macrophages as well as NK-cells--clearly related to therapy.

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This report describes some experimental and clinical studies showing the following: (1) in animals under protection of mesna the dose of ifosfamide (Ifo) can be increased significantly; (2) fractionated administration of Ifo, cyclophosphamide (CPA), or the stabilized metabolite of cyclophosphamide (ASTA Z 7557) is less toxic than single push-injection of the same total daily dose and therapeutically more effective; and (3) in humans under the protection of mesna the continuous infusions of ifosfamide over 5 days leads to an increase of the MTD compared with single daily short-term infusion and responses in some solid tumors, e.g., soft tissue sarcomas.

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ASTA Z 7557 is a stabilized cytostatic metabolite of cyclophosphamide which forms crystals at room temperature and releases 4-OH-cyclophosphamide in aqueous solution. The LD50/30 in mice after push injection is 417 mg/kg, after fractionated administration (q 6 hours X 4) 794 mg/kg. Daily treatment times 5 gives a LD50/30 value of 200 mg/kg. Depression of nucleated bone marrow cells and of leukocytes in the peripheral blood is observed after treatment. Recovery is slow. This holds true for push and fractionated administration. ASTA Z 7557 is a powerful cytostatic drug for treatment of an Ehrlich ascites tumor, a Lewis lung and a mammary carcinoma. Of two human tumor xenografts a malignant amelanotic melanoma responded with slight growth delay, whereas a gastric cancer did not.

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Oral feeding of mice with hypercaloric diets inhibited growth of a hyperdiploid Ehrlich ascites tumor significantly and modified proliferation kinetics of tumor cells if feeding started 7 days before tumor transplantation. Furthermore, the tumor take rate was significantly reduced. The 4 hypercaloric diets contained as main energy sources carbohydrates, or unsaturated fatty acids, or saturated fatty acids, or a mixture of these substrates. Inhibition of tumor growth was not observed if hypercaloric feeding started on the same day the tumor transplantation occurred. Tumor bearing animals lived significantly longer compared to controls if they are on a hypercaloric diet with unsaturated fatty acids as main energy source. Survival was not influenced by the time feeding started. That means that partial prevention of cachexia was the main reason for longer survival. Feeding with a diet poor in proteins led in both experimental sets to a statistically not significant shortening of the median survival time compared to controls.

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This paper deals with experimental investigations concerning the composition of a cytostatic three-drug-protocol in diploid Ehrlich-Ascites-Tumor (EAT) cells in vivo at a far advanced stage of the disease. Hydroxyurea (HU) and vincristine (VCR) were used in very low doses to induce a modification of the growth pattern of tumor cells alike partial synchronization. Adriamycin (ADM) was selected as cytocidal drug during DNA synthesis of the partially synchronized cells. It was found that the sequential combination of HU and VCR (first HU and 12 h thereafter VCR) caused the greatest alteration of growth pattern compared with other combination protocols. A further statistically significant increase of the degree of synchrony was observed after a second VCR administration -- 22 h after HU. By means of this protocol the EAT was subdivided into two proliferating subpopulations, a diploid and tetraploid one. The tetraploid population resulted from surviving cells being not able to perform dytokinesis correctly, so that polynuclear cells and cells with a large single nucleus containing tetraploid DNA values were created. With respect to therapy, the administation of ADM at the time of DNA synthesis of the partially synchronized cells resulted in a statistically significant prolongation of the mean survival time and in 30% of cures of the animals. The dosage of ADM was 2.6 mg/kg, i.e., a nonlethal dose (50% of the LD10). Other combinations, i.e., simultaneous or reversed sequential combinations, did not show any therapeutic improvement compared to single drug therapy of ADM.

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