In conjunction with two phase I clinical trials, we have investigated the pharmacokinetics of marcellomycin (MCM), a new class II anthracycline antibiotic, in nine patients with normal renal and hepatic functions and no third-space fluid accumulation. MCM was infused IV over 15 min at a dosage of 27.5, 40, or 50 mg/m2. Plasma and urine samples were collected up to 72 h. MCM and metabolites were assayed by thin-layer chromatography and quantified by specific fluorescence. The disappearance of total MCM-derived fluorescence from plasma followed first-order kinetics and lacked the rebound in total fluorescence that has been described for the structurally similar agent, aclacinomycin A. After 40–50 mg/m2, the peak MCM concentration in plasma was 1.67±0.61 μM; MCM disappeared from plasma in a triexponential fashion and was undetectabel by 48 h after infusion. The area under the plasma concentration-time plot (AUC), including the infusion time, was 1.11±0.39 μMxh; plasma clearance of MCM was 1.50±0.88 l/min/m2. Five other fluorescent compounds were consistently observed in plasma. M2 was a contaminant present in the parent drug. P1 and P2 were conjugates of MCM and M2, respectively. G1 and G2 were aglycones. The peak concentrations of the metabolites were 25% or less or the peak concentration for MCM, but their persistence resulted in higher AUCs than that for MCM. For the dosage of 27.5 mg/m2, fewer data were available; but the pharmacokinetics of MCM and metabolites appeared to be similar to that at higher dosage. Urinary excretion of total fluorescence amounted to 8.0%±1.6% of the total dose at 40–50 mg/m2, and to 7.0%±2.3% at 27.5 mg/m2. No correlation was detected among the various pharmacokinetic parameters and toxicities encountered in these patients.

4′-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA) and N-(phosphonacetyl)-l-aspartate (PALA) are two new anticancer agents that have been recently introduced into clinical investigation. This review summarizes the preclinical information that has accumulated with these compounds as well as the very preliminary data presently available from early clinical trials. This information indicates the promising potential of m-AMSA and PALA in the treatment of cancer.

Alizapride is a methoxy-2-benzamide derivative three times more potent than its parent compound, metoclopramide, as an antagonist of apomorphine-induced emesis in dogs. The antiemetic activity of alizapride plus dexamethasone (DXM) was compared with that of placebo plus DXM in a randomized, double-blind, crossover study in cancer patients receiving cisplatin (DDP). Alizapride, given at the maximally tolerated dose of 4 mg/kg x 5, or placebo was given in a sequence determined by randomization during two successive, identical courses of antitumor chemotherapy. The antiemetic treatment was given 30 min before and 1.5, 3.5, 5.5, and 7.5 h after starting. DXM, in a dose of 12 mg, was given IV with the first administration of alizapride or placebo. A total of 39 patients completed the two courses of chemotherapy. The severity of gastrointestinal symptoms was influenced by previous treatment but not by the treatment sequence. Although our overall results suggest that alizapride does not add to the activity of DXM against DDP-induced amesis, a statistically significant difference favoring alizapride plus DXM was found among patients with the lowest gastrointestinal tolerance to DDP: women, patients under 50 years of age, and patients pretreated with chemotherapy including DDP and non-DDP agents. Side effects consisted of orthostatic hypotension, which was symptomatic in two patients, and a single occurrence of severe extrapyramidal syndrome. We conclude that alizapride is more active than placebo when combined with DXM for DDP-induced emesis in patients at high risk of severe nausea and vomiting. The severity of the side effects in this study indicates that a dose reduction of alizapride might be appropriate for further studies.

A total of 185 eligible patients with advanced inoperable squamous cell carcinoma of the head and neck were randomized into two groups; the cisplatin, methotrexate, bleomycin, and vincristine (CABO) group received cisplatin (50 mg/m2; day 4), methotrexate (40 mg/m2; days 1, 15), bleomycin (10 mg; days 1, 8, and 15), and vincristine (2 mg; days 1, 8, and 15) and the ABO group received methotrexate, bleomycin and vincristine in the same doses on days 1, 8, and 15. After three courses, patients in both arms received weekly methotrexate as maintenance therapy; those 34 patients with previously untreated locoregional disease went off the study because of subsequent locoregional treatment in form of radiotherapy +/- surgery. The complete response rate was 16% in patients receiving CABO, compared with 5% among patients given ABO. The corresponding overall response rates were 50% and 28%, respectively (P = 0.003). Among patients with recurrent or metastatic disease, progression was delayed in patients receiving CABO (median, 18 weeks) compared to those receiving ABO (median, 14 weeks) (P = 0.07), but there was no difference in survival time. Myelosuppression consisted mostly of leukopenia, which was seen in 67% of the CABO patients versus 47% in the other arm. Myelosuppression-associated infection and hemorrhage led to death in two patients in the CABO treatment group and six patients in the ABO treatment group. Nausea and vomiting, mostly of grades 1 or 2, occurred in 93% of the patients given CABO and 44% of those receiving ABO. Other toxic effects--neuropathy, alopecia, stomatitis, constipation, fever/chills, diarrhea, cutaneous alterations, and renal impairment--occurred equally in the two treatment groups. This study underlines the role of cisplatin in head and neck cancer, although no impact on survival could be demonstrated. It also supports indirectly the superiority of combination chemotherapy over single-agent treatment for this disease.

The cytotoxic effect of daunorubicin, carminomycin, idarubicin and the major metabolite of idarubicin in man, 4-demethoxydaunorubicinol, was investigated in a human normal progenitor myeloid stem cell assay and in a human tumor stem cell assay. Against normal myeloid progenitor cells, idarubicin and carminomycin were equally potent; both agents were significantly (P ⩽ 0.01) more potent than daunorubicin. Idarubicin was approx. 2.5 times more potent than 4-demethoxydaunorubicinol. Against malignant tumor cells, 50% cell kill after exposure to idarubicin was observed in four out 24 samples; this inhibition occurred at a drug concentration of 0.1 μg/ml. Two of the samples sensitive to idarubicin were also sensitive to 4-demethoxydaunorubicinol at a concentration of 0.1 μg/ml. Overall, idarubicin was active against two out of six ovarian carcinomas and against one out of three breast carcinomas. Our data confirm that 4-demethoxydaunorubicinol may play a role in the biological activity of idarubicin.

Many in vitro investigations with anticancer agents are performed at concentrations equal to the peak concentrations or fractions of the peak concentrations achieved in human plasma after administration of these agents. In an effort to develop an in vitro test capable of predicting these peak plasma concentrations prior to the completion of pharmacokinetic studies, the effect of several classes of anticancer agents against normal human bone marrow myeloid progenitor cells (CFU-GM) was studied. The investigated agents included anthracycline antibiotics, cisplatin and its analogs, anthracene derivatives and two flavone acetic acid derivatives. The CFU-GM were exposed to these agents for 30-60 min. An exponential relationship between drug concentration and CFU-GM growth was observed for all compounds with the exception of the flavone acetic acid derivatives which were inactive. For the latter two compounds, an inhibition of CFU-GM growth was observed after continuous exposure. When compared to the plasma concentrations after parenteral administration of these agents, there was a very good agreement between 1/10 of the peak plasma concentration and the concentration inducing a 90% inhibition of the CFU-GM growth for the anthracycline antibiotics and anthracene derivatives. In contrast, for cisplatin and its analogs, there was a better agreement between 1/10 of the peak plasma concentration and the concentration inducing a 10% inhibition of CFU-GM growth. The combination of concentrations inducing inhibitions of 10 and 90% of the CFU-GM growth provides a range of concentrations that predict reasonably well the peak plasma concentrations of several anticancer agents and that could be used as guides for other in vitro investigations.

The in vitro evaluation of new antineoplastic agents has been advocated as a method of selecting drugs for Phase I-II trials in patients. This paper is an attempt to validate, in an unbiased manner, the so-called in vitro Phase II clonogenic assay with regard to its predictive power in the clinic. Breast and ovarian cancer were chosen because of the relatively large number of drugs clinically evaluated for these diseases; 298 patients were studied. For metastatic breast cancer 12 drugs, six clinically active and six inactive, were tested. It was found that in patients without prior chemotherapy, there is an association between results in vitro and in vivo. In metastatic ovarian cancer, 11 drugs, four of which are known to be clinically inactive, were studied. The same positive association was seen for patients without prior chemotherapy. The implications of these findings are discussed.

Forty-two patients with malignant melanoma were treated with doxifluridine, 4000 mg/m2 daily ×5, repeated every 3 weeks. The daily dose was reduced to 3000 mg/m2 in patients who had experienced severe myelosuppression with prior chemotherapy. A total of 35 patients were evaluable for response, and 25 of these received two or more courses. Two responses were observed. Toxicity mainly took the form of nausea, vomiting, stomatitis, dizziness, ataxia, and fatigue. Mild leukopenia was frequent (43%). Nadir counts <1.5×109/l leukocytes or 50×109/l platelets were seen in 7% and 2% of the courses respectively. Doxifluridine has no useful activity against malignant melanoma.

The activity of menogaril and its major metabolite in animals and humans, N-demethylmenogaril, has been investigated in the human stem cell assay as developed by Salmon et al. Among 31 evaluable samples, four were sensitive to menogaril, including one which responded to N-demethylmenogaril. Three samples resistant to menogaril responded to N-demethylmenogaril. None was sensitive to doxorubicin. Overall, one out of seven ovarian samples and one out of three breast samples responded to menogaril. Our data confirm the in vitro activity of menogaril in ovarian and breast cancer; in addition, they suggest incomplete cross-resistance between doxorubicin and menogaril and, considering the concentrations of N-demethylmenogaril in animals and humans, a minor role for this metabolite in the overall antitumor activity of the parent compound.

Thirty-six evaluable patients with locoregionally recurrent or metastatic squamous cell carcinoma of the head and neck were treated with a combination of mitomycin (10 mg/m2 i.v. day 1), fluorouracil (500 mg/m2 i.v. days 1 + 8) and hydroxyurea (1 g/m2 orally days 2–14). Thirty-three patients had received prior radiation therapy and 34 prior chemotherapy. Only two patients exhibited a partial response. Hematological toxicity was substantial, with three patients experiencing leukopenia below 1000/mm3 and seven patients experiencing thrombocytopenia below 25,000/mm3. There were four cases of treatment-related bleeding and one infection. Other side-effects were mild to moderate. Low antitumor activity and substantial toxicity preclude further evaluation of this regimen in head and neck cancer.

This phase II clinical trial was conducted in a series of patients with advanced breast cancer, refractory to conventional chemotherapy. The therapeutic regimen consisted of a combination of cisplatin 100 mg/m2, given as a 24-hr infusion on day 1 and vindesine (VDS) 2 mg/m2, i.v. bolus on days 1 and 8. VDS injection was omitted on day 8 in patients with poor bone marrow reserves (prior extensive irradiation). Courses were repeated at 4-week intervals until documented disease progression. Among 46 evaluable patients, there were two complete and seven partial remissions for an overall response rate of 20%. These responses lasted for a median of 21 weeks (range 8–89 weeks). Remission rates according to the predominant metastatic site were as follows: soft tissue, 38 (38%); bone, 06 (0%); viscera, 632 (19%). Transient myelosuppression and gastrointestinal intolerance were almost universal. Renal function impairment and neurologic manifestations were frequently encountered but these adverse reactions were generally mild. Significant antineoplastic activity in far-advanced and heavily pretreated patients warrants further evaluation of this regimen at an earlier stage of the disease.

The pharmacokinetics of esorubicin, a new anthracycline antibiotic, was investigated in conjunction with a phase I clinical trial. The drug was administered to 12 patients as an intravenous bolus at a dose of 20 to 40mg/m2. All patients had normal renal and hepatic functions and no third space fluid accumulation. Plasma and urine samples were assayed by HPLC. The peak plasma concentration of esorubicin was 0.74 ± 0.57 μM (mean ± SE). Esorubicin disappeared from plasma according to a tri-exponential pattern with a terminal half-life of 20.4 ± 7.3 hr. The area under the plasma concentration versus time curve was 0.64 ± 0.31 μMxhr. Total body plasma clearance was 45.5 ± 26.8 liter/min/m2 and the apparent volume of the central compartment, 41.0 ± 24.8 L. A single metabolite, 4′-deoxydoxorubicinol, was detected in plasma. This metabolite was observed in 5 patients only and its mean peak concentration was 0.029 ± 0.017 μM. The area under the plasma versus concentration time curve for 4′-deoxydoxorubicinol was 0.02 ± 0.014 μMxhr. The urinary excretion of total fluorescence within 5 days of therapy was 7.3 ± 1.3% of the administered dose. Esorubicin represented more than 80% of the excreted anthracyclines. As in plasma, 4′ -deoxydoxorubicinol was the only metabolite detectable in urine. No correlation between the various pharmacokinetic parameters and drug-induced toxicity was observed in this small group of patients.

A broad phase II trial of elliptinium was conducted in 105 evaluable patients with advanced solid tumors. The drug was given as a 60-90-min i.v. infusion at a weekly dose of 100 mg/m2. Of 36 breast cancer patients, one achieved complete and six achieved partial response for an overall response rate of 19%. Responses lasted for 12-56 weeks from initiation of therapy. There was also one partial response among 21 patients with squamous cell carcinoma of the lung. No response could be obtained in 17 patients with colon cancer, 13 patients with head and neck cancer and 18 patients with a wide variety of other malignancies. Myelosuppression was minimal. Nausea and vomiting were the most frequent toxic effects. The drug also produced serious xerostomia and acute intravascular hemolysis. Asthenia was common. Other adverse reactions included fever and chills, transient neurologic and cardiovascular manifestations and renal function impairment. Additional work is needed to define optimal modes of drug administration.

Peritoneoscopy is widely used as a diagnostic procedure to detect hepatic metastases. Liver involvement may be demonstrated by biopsy and microscopic examination. In contrast, normal biopsy is not a proof that the liver is free of invasion. The risk of false negative findings at peritoneoscopy is evidently related to the selection of patients (Bleiberg et al. 1978). Thus the risk may be noticeably lower if the procedure is performed to confirm that a malignant disease is still operable than if it is used because of altered liver function tests at the advanced stage of the same disease. These effects of the prevalence in diagnostic tests must also be taken into consideration for predictive tests.