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Human mononuclear phagocytes were isolated from peripheral blood, peritoneal exudate and early lactation milk by adherence on microexudate-coated plastic and exposure to ethylene diamine tetracetic acid. Their cytolytic activity was measured as 3H-thymidine release from prelabelled target cells over 48-72 hr and cytostasis was evaluated in a spectrophotometric 72-hr assay. The murine SV40-transformed mKSA-TU5 line and the human E cell line, derived from an ovarian carcinoma, were employed as targets. Peripheral blood monocytes, in vitro-matured monocyte-derived macrophages, peritoneal macrophages and milk macrophages were all significantly cytolytic and cytostatic on these target cells at attacker to target cell ratios ranging from 5:1 to 40:1. When monocytes were cultivated in vitro, no loss of cytocidal capacity occurred over the first 10 days of culture, whereas later on, when epithelioid and giant cells predominate in the cultures, mononuclear phagocytes had little cytotoxic activity. Adherent cells obtained from cord blood or from the peripheral blood of old donors had natural cytotoxicity similar to monocytes obtained from young adult volunteers. Peripheral blood monocytes and peritoneal macrophages showed enhanced cytolytic activity after exposure to partially purified human fibroblast interferon. These experiments suggest that in the human mononuclear phagocyte series cytotoxicity on tumour cells is not restricted to circulating monocytes but is also expressed by macrophages obtained from diverse anatomical sites.

Peripheral blood monocytes and macrophages from ascitic or solid tumors were obtained from 50 patients with advanced (Stage III or IV) ovarian carcinoma. Blood monocytes and peritoneal macrophages from 76 patients undergoing surgery for benign gynecological diseases were used as controls. Macrophages were 30% (range 0.2-6.2) and 2% (range 0.2-4) of mononuclear cell suspensions from ascitic and solid tumors, respectively. Cytolytic activity was measured as release of [3H]-thymidine from prelabelled mKSARU5 (TU5) target cells at an effector to target cell ratio of 20:1. Peripheral blood monocytes and tumor-associated macrophages had baseline cytotoxicity lower than or similar to that of control peripheral blood and peritoneal macrophages respectively. In vitro exposure to partially purified human fibroblast interferon, lymphokine supernatants or endotoxin augmented the cytotoxicity of mononuclear phagocytes, and no significant difference was observed between control and ovarian cancer effector cells from peritoneal effusions. In four patients, macrophages were isolated from the solid tumor or from the malignant effusion and tested in parallel: in two out of four subjects, macrophages from the solid neoplasm showed defective cytotoxicity compared to ascites effector cells from the same subject. When primary ovarian carcinoma cultures were used as targets, tumor cells from two out of five patients tested were relatively resistant to activated macrophage cytotoxicity. Thus, tumor-associated macrophages from ascitic or solid ovarian neoplasms showed no evidence of activation, in terms of spontaneous cytotoxicity or responsiveness to stimuli: it appears unlikely that small numbers of non-activated macrophages present within primary ovarian carcinomas act as a significant mechanism of restraint of neoplastic growth, at least at this anatomical site.

Twenty-four patients with a variety of solid tumors entered a Phase I trial with 4-demethoxydaunorubicin, a new analogue of daunorubicin. The drug was given as a single oral dose of 10-60 mg/m2 repeated every 3-4 weeks. Leukopenia was the dose-limiting toxicity. Other toxic effects included mild to moderate nausea and vomiting. Sixty mg/m2 was found to be the maximum tolerated dose in patients with fair tolerance to chemotherapy and normal liver function. Similar hematologic toxicity was reported in patients with very extensive prior chemotherapy or diffuse bone and/or liver metastases receiving 50 mg/m2. However, the wide range of the WBC nadirs reported with the same dose in 'good risk' cases, suggest that 40 mg/m2, increased up to 50 mg/m2 in the absence of significant myelotoxicity, could be more safely proposed as starting dose for Phase II trials. Pharmacokinetic studies were performed in five patients given a single dose of 40-60 mg/m2. IMI-30 (NSC 256439) appears to be rapidly absorbed and rapidly eliminated from plasma by means of a rapid and extensive biotransformation to 13-OH-idarubicin. The 13-dihydroderivative was present at higher and more prolonged levels than the parent compound, with an elimination half-life of about 40 hours.

Sixteen patients with advanced colo-rectal cancer were treated with the combination methyl-CCNU, vincristin, 5-fluorouracil and streptozotocin (MOF-Strepto). Seven cases were previously untreated. A partial remission was observed only in one patient (6%, confidence limits to 95%: 1-17%). Marked gastrointestinal and hematologic toxicity was registered. Based on this experience the authors are unable to confirm other pilot studies claiming major antitumor activity for MOF-Strepto in the treatment of advanced colo-rectal cancer.

Eleven patients with heavily pretreated acute leukaemia were treated with 4-demethoxydaunorubicin. Dosages were escalated from 7 mg/m2/d to 15 mg/m2/d for 3 consecutive days. One patient achieved a partial remission and antitumor activity was seen in most other patients. Stomatitis was dose-limiting at 15 mg/m2. Phase II trials are warranted and we propose a schedule of 12 mg/m2/d for 3 consecutive days.

Etoposide (VP16) levels were determined by high-performance liquid chromatography assay in plasma, urine, and surgical specimens of patients with choriocarcinoma undergoing surgery after a dose of 100 or 200 mg/m2 given as a 1-hour infusion. The drug disappeared from plasma biexponentially, with a terminal half-life of 4.1 +/- 0.4 hours, an apparent volume of distribution of 9 +/- 1.1 L/m2, and clearance of 21.5 +/- 3.1 ml/minute/m2. Fifty and 740 minutes after the end of VP16 infusion, the drug concentrations in myometrial carcinoma or in normal myometrium were approximately 40%-50% of those in plasma; 25-180 minutes after the end of drug infusion, the concentrations of VP16 in lung metastases amounted to 19%-43% of those in plasma, whereas in normal lung, the concentrations of VP16 were 38%-61% of those in plasma. In subcutaneous tissue, VP16 levels were much lower than in plasma (about 5%-27%). About 50% of VP16 was eliminated in the urine as unchanged drug, glucuronide, or sulfate.

Pharmacokinetics of teniposide (VM26) after each of three doses were investigated by high-performance liquid chromatographic assay in eight patients with ovarian cancer with normal liver and renal functions. Treatment consisted of a first dose of 100 mg/m2 iv as a 1-hour infusion (Day 1), a second dose of 150 mg/m2 iv as a 1-hour infusion (Day 8), and a third dose of 150 mg/m2 as an approximately 1-day infusion (Day 22). Disappearance of VM26 from plasma followed a biexponential decay pattern. The mean terminal half-life (+/- SE) was 6.9 +/- 0.9 hours after the first dose, 6.1 +/- 0.7 hours after the second dose, and 9.7 +/- 1.4 hours after the third dose. VM26 levels in ascites were lower than those in plasma in the first hours after drug administration, but by 24 hours they were similar or slightly higher. Urinary elimination of VM26 as unchanged drug amounted to less than 10% of the dose.

Data of five phase II clinical trials on iproplatin and carboplatin, conducted by the ECTG, have been pooled in order to evaluate the extent of toxicities of these compounds. One hundred and seventy patients treated with iproplatin and 65 patients treated with carboplatin were evaluable. Most of them (81%) had been previously treated with chemotherapy. Doses ranged from 180 to 300 mg/m2 every 4 weeks for iproplatin, and from 350 to 450 mg/m2 every 5 weeks for carboplatin, according to the initial status of the patient. WHO criteria were used to grade toxic effects. Weekly blood counts were performed, and lowest observed counts were analysed by non-parametric methods. Censored data were analysed by actuarial methods. Thrombocytopenia was the dose-limiting toxicity and was dose related. Leucopenia was less severe. The risk of thrombocytopenia varied largely amongst patients, and could be predicted from the initial platelet count, the initial creatinine level and prior therapy with alkylating agents. The cumulative risk increased with the total dose, but with a decreasing hazard rate, and without additional delay to platelet recovery. Nausea, vomiting and diarrhoea were the most frequently observed non-haematological side-effects, and were more severe with iproplatin than with carboplatin. Peripheral neuropathy was observed in some cases, but could be due to prior treatments. Renal toxicity did not cause major problems. Our results confirm the findings of the phase I trials: thrombocytopenia is dose-limiting for both drugs, and renal side-effects are negligible. The risk model of thrombocytopenia, consistent with Egorin's model for carboplatin, could serve as a basis for dose adjustment. The feasibility of the scheme could be insufficient for prolonged treatment.

The distribution of hexamethylmelamine (HMM) was investigated in surgical biopsies from 12 patients with pelvic cancer who were given an oral dose of 200 mg at 2-24 hours before the operation. The highest concentrations of HMM were found in tissues, such as omentum and subcutaneous tissue, that have a predominant lipidic component. HMM concentrations in the primary tumor were lower than in other tissues and were similar to those in plasma. HMM concentrations in metastases appeared to be higher than in the primary tumor, and in metastases with a diameter less than 3 mm, drug levels were two to ten times those in larger ones. Plotting the HMM concentrations versus time, utilizing the data from different patients, the elimination half-lives were found to be 9.05, 8.82, and 8.53 in plasma, tumor, and subcutaneous tissue, respectively.