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A phase 1 study of a new ribonucleotide reductase inhibitor, didox, was performed by administration of escalating doses of the drug by slow i.v. injection. Thirty-four patients with unresponsive metastatic carcinoma received the drug. There were 13 escalations of dosage, from a starting dose of 192 mg m-2 to 10 g m-2. Dose limiting toxicity was encountered at 7.5 g m-2 where disturbances of hepatic and renal function were observed, in addition to severe gastrointestinal toxicity. Pharmacokinetic studies showed that a peak level of didox was achieved within 5 minutes of injection. At 1,728 mg m-2 the data best fitted a 2 compartment open model, with a mean serum alpha t1/2 of 5.2 min, with a beta t1/2 of 41.3 min. Less than 10% of the drug was excreted unchanged in the urine and the majority of this excretion was within 6 h. Didox can therefore be safely given by slow i.v. injection at a dose of 6 g m-2.

Eight onco-developmental proteins have been measured in the serum of women prior to their operation and treatment for ovarian cancer. Alpha-foetoprotein, CEA, hCG and PAPP-A were not often elevated whereas CPAP, SP1, CanAg 50 and CA 125 were. Many of our findings differed from those of previous workers, possibly due to differences in clinical material and analytical technique. We conclude that large profiles of tumour markers are no longer of use in the investigation of ovarian cancer. At the present time we think that CA 125 could prove the most useful marker in the investigation of ovarian cancer.

We have conducted a Phase I and initial clinical pharmacological evaluation of LM985, the first of a series of compounds based on the flavone ring structure to be considered for clinical trial in malignant disease. The drug was administered i.v. to 26 patients with advanced cancer on an every-21-day schedule. Patients were treated at 14 dosage levels ranging from 10 to 1500 mg/m2. Dose limiting toxicity was identified as acute reversible hypotension occurring during drug infusion; no leukopenia, alopecia, hepatic toxicity, or renal toxicity was observed, but at the higher dose range, mild sedation was apparent. Twenty patients had measurable disease and were evaluable for response. One patient with colorectal carcinoma had stable disease after three courses of LM985; however, no other responses were seen. Pharmacokinetic and in vitro drug degradation studies imply that the ester LM985 is hydrolyzed to LM975 (flavone acetic acid) rapidly in vivo. LM975 is active in a variety of animal tumor models, but it does not have the cardiovascular side effects seen with LM985 (hypotension and bradycardia) in pithed or anesthetized rats. We would recommend that LM975 be considered for clinical trial, because it seems likely that substantially higher doses of LM975 than of LM985 can be given without dose limiting cardiovascular toxicity.

Between 1973 and 1977, 247 patients with malignant teratoma have been treated in two units in London. Seventeen have developed brain metastases, an overall incidence of 6.2%. The median survival from diagnosis of cerebral metastases is 6 weeks and all patients except one have died. The survivor is disease-free 12 months after completing treatment, which included extensive use of chemotherapy, surgery and radiotherapy. Serum gonadotrophin (HCG) and alpha-foetoprotein (AFP) estimations have been performed in 264 patients as a means of monitoring the effects of therapy. In 42 patients (37 of whom had Stage IV disease) the peak HCG level was greater than 10(4) iu/l, and the incidence of brain metastases in this group was 26%, significantly higher than in the group with HCG levels below 10(4) iu/l, for which the incidence of cerebral deposits was 1.8% (P less than 0.0001). No significant correlation was seen between peak AFP levels and the incidence of brain metastasis. With the aim of improving results by earlier diagnosis, cerebrospinal fluid (CSF) specimens have been examined for HCG and AFP levels in 56 subjects, 9 of whom had brain metastases. A serum: CSF HCG ratio less than 40 is an accurate indication of the presence of brain metastases, and may have considerable predictive value. However, false-negative serum: CSF HCG rations (greater than 40) frequently occur in patients with proven brain deposits. Estimation of AFP in spinal fluid has not contributed to the early diagnosis of brain metastases in malignant teratoma.