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Direct Coombs tests were performed in 265 patients with solid tumors, leu-kemias and malignant lymphomas. The frequency of highly positive Coombs tests varied from 5.52 in the solid tumors (13 % for the carcinomas) to 52 % in chronic lymphotic leukemia. A secondary autoimmune hemolytic anemia, without antibody, was present in 2 cases of solid tumors and in one case of Hodgkin's disease. A dubious or slightly positive Coombs test was frequently observed without signs of increased hemolysis. On the other hand, a strongly positive Coombs test was associated with an acute hemolysis in most cases but in patients with macroglobulinemia. Biological tests usually considered as characteristic for secondary hemolytic anemia (reticulocytosis, unconjugated bilirubin, urinary excretion of urobilinogen, serum iron, granulopoiesis/erythropoiesis ratio) have not an unequivocal significance : they may be normal in cases with true hemolytic anemia or abnormal in patients with a normal survival time of the red cells. The presence of more than 2 abnormal tests is however indicative for the diagnosis of hemolytic anemia, especially if there is no liver deficiency.

Resume Quatre-vingt-quatorze cos de tumeurs solides ont ete traites par le Natulan. Un effet objectif certain a ete observe dans 3 cas d'epithelioma de la tete et du cou, 3 cas de cancer du poumon, 1 cas de carcinome de l'ovaire, 1 cas de carcinome du colon et 1 epithelioma epidermoide d'origine inconnue. Deux effets objectifs probables ont ete observes en outre dans des epitheliomas de la tete et du cou. La toxicite hematologique a ete moderee et toujours reversible, sauf chez 3 patients qui sonl marts d'infection avec leucopenie. La toxicite digestive a ete le principal inconvenient du traitement. The hematological toxicity has been moderate and always reversible except in three patients who died of infection with leukopenia. The main drawback of the treatment consisted in gastrointestinal toxicity.

Six intracarotid artery infusions of DTIC were performed in 4 patients with invasive malignant melanoma of the maxillo-facial region. A total dose of 3.5 to 7 g was well tolerated. Only 1 patient who received 9.5 g in 25 days developed a reversible bone marrow depletion. Two out of the 4 patients presented a transient 50 % tumor surface regression, but no response was seen after the second infusion. Of the 2 remaining patients, 1 had no measurable effect and 1 experienced tumor progression.

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.

The anticancer activity of carminomycin was investigated in a human tumor cloning assay. No efficacy could be identified in the WiDr and the MCF7 cell lines which were highly responsive to doxorubicin. In addition, drug testing experiments were carried out in samples of various malignancies freshly obtained from 86 patients of whom 54 had not received prior anthracyclines. A reduction in the number of tumor colony forming units by 50% or more was seen in 1/26 breast cancers, 1/22 ovarian cancers and 1/7 melanomas. Cross-resistance studies indicated that eight tumors were responsive to doxorubicin only and one to carminomycin only whereas two were sensitive to both and 73 were resistant to both. This in vitro Phase II study corroborates the disappointing clinical results achieved with carminomycin.

Twenty-three patients with advanced solid tumors received 9 -hydroxy- 2N -methyl-ellipticinium acetate at a single daily i.v. dose of 15–80 mg/m 2 for 5 consecutive days , repeated every 3 weeks . One partial and one minor response were achieved in two patients with breast cancer. Dryness of the mouth was dose-related and dose-limiting. Local phlebitis was also dose-related and frequently severe at the highest dose levels. Other non-hematologic toxic effects were essentially mild to moderate and included nausea, vomiting, diarrhea, stomatitis, fever, weakness, transient renal and hepatic impairment, alopecia and chest pain. Minimal myelosuppression was encountered. It appears that 60 mg/m 2 /day is the maximum tolerated dose with a five-day schedule. According to our findings, this schedule does not seem to offer any advantage over the previously tested weekly administrations.

Eighteen adult patients with solid tumors were treated with oral menogaril, a new anthracycline antibiotic active against human breast cancer after intravenous administration. The drug was given orally on 3 consecutive days every 4 weeks at doses ranging from 50 to 175 mg/m2/day. Reversible and dose-related leukopenia was the dose-limiting toxicity. At doses from 50 to 150 mg/m2/day, non-hematologic side effects of oral menogaril were unfrequent and mild and consisted of nausea and vomiting (1 patient), alopecia (2 patients), mucositis (2 patients) and liver function test abnormalities (3 patients). The only patient treated at a daily dose of 175 mg/m2 developed grade IV leukothrombocytopenia, with fever and gastrointestinal bleeding. This was followed by heart insufficiency and the patient died from multisystem organ failure. A dose of 150 mg/m2/day for 3 consecutive days is recommended for phase II trials with oral menogaril.

Since 1976, a double blind study has been conducted to assess the value of levamisole as adjuvant treatment to surgery for non-small cell carcinoma of the lung. Fifty-one patients were evaluable with a minimal follow-up period of 1 yr. No difference could be observed between the two groups in the duration of the survival and of the disease free survival. In cases of complete resection without any lymph node involvement, an increase of the free interval was observed. This was not statistically significant.

4'-Deoxydoxorubicin is a new anthracycline derivative. Experimentally, the drug shows efficacy against doxorubicin-resistant malignancies and, as compared to the parent compound, it has reduced potential for heart damage. This Phase I trial was conducted with a single dose intermittent schedule. 4'-Deoxydoxorubicin was given by rapid i.v. administration at doses of 20, 30, 35 and 40 mg/m2. A total of 25 adult patients with a variety of solid tumors received a median of two courses (1-4). Leukopenia was dose-related and dose-limiting. Occasionally severe thrombocytopenia was also encountered. Nonhematological toxic effects were mostly mild to moderate and were qualitatively similar to those commonly reported with doxorubicin. The frequency of local reactions was apparently increased but the incidence of alopecia and gastrointestinal distress was noticeably lower. There were no acute or chronic drug-induced cardiac effects. Antitumor activity was suggested in a patient with a carcinoma of the cardia. For Phase II trials, doses of 35 and 30 mg/m2 every 3-4 weeks may be recommended in good-risk and poor-risk patients, respectively.

The single agent activity of chlorozotocin was evaluated in advanced colorectal cancer not previously treated with chemotherapy. The drug was given at a dosage of 200 mg/m 2 i.v. repeated every 6 wk . Of 23 evaluable patients, 2 achieved a partial response lasting 4 and 5 months respectively. With this dosage regimen, chlorozotocin produced essentially nausea and vomiting in one-half of the patients as well as myelosuppression that varied with performance status. Our findings suggest that the therapeutic index of chlorozotocin is similar to that of other conventional nitrosourea derivatives in this disease. However, additional experience is needed to definitely assess how cumulative is their respective bone marrow toxicity.

The diethylaminoester of flavone acetic acid (LM985) is a new anticancer agent with curative effects against slow growing murine tumors. Thirty-one adult patients with solid tumors received a total of 57 courses of LM985 given on days 1 and 8 every 4 weeks. The drug was given as a short infusion (1-2 hr) at doses ranging from 120 to 1900 mg/sq.m/day. The dose-limiting toxicity consisted of acute expressive aphasia; this neurotoxicity usually appeared at the end of the infusion and resolved spontaneously within a few minutes to 1 hr after the end of the infusion. In some patients, neurotoxicity was avoided by reducing the infusion rate. Neurotoxicity was observed in 5 out of 6 patients receiving 960 mg/sq.m over 1 hr and in 3 out of 3 patients receiving 1900 mg/sq.m over 2 hr. The drug did not induce any significant myelosuppression. Other side-effects were very mild and consisted mainly of occasional nausea and/or vomiting at all dose levels. One patient with breast cancer resistant to several hormonal and chemotherapy regimens had stable disease for 6 months. LM985 was detected in plasma in very small concentrations (0-2.5 micrograms/ml) but there was extensive formation of flavone acetic acid (peak concentration ranging between 8.3 and 64 micrograms/ml). A dose of 1500 mg/sq.m on days 1 and 8 every 4 weeks could be recommended for phase II studies with LM985; however, since LM985 is a prodrug of flavone acetic acid, phase II studies with LM985 should not be activated prior to the completion of the ongoing phase I trials with flavone acetic acid, which may be devoid of the acute toxicity of LM985.

Fourty-three patients with head and neck epidermoid carcinomas were treated with combination chemotherapy consisting of vinblastine (VLB) 4 mg/m 2 i.v., methotrexate (MTX) 60 mg/m 2 i.v. and bleomycin (BLM) 15 mg i.v. day 1 and 8 , q 28 days . Dose limiting toxicity was clearly hematological: leukopenia was more severe than thrombopenia and 5 patients died of septicemia associated with WBC 1000 . Other toxicities included mucositis, skin rash, fever, nausea and vomiting. Alopecia was rare. Treatment was stopped in two patients because of reversible pulmonary toxicity. There was no significant hepatic or renal toxicity. Ten patients were inevaluable: because of loss of follow-up or refusal of treatment ( 9 ) or intercurrent radiation therapy ( 1 ). Out of 33 fully evaluable patients, there were 9 ( 27% ) responders: 3 complete responses lasting 8, 16+, 18+ months and 6 partial responses (> 50% decrease in tumor size) for a median duration of 4 months . Stabilisation of disease (no change or regression 8 ( 23% ), progression of disease in 8 ( 23% ), early death in 3 ( 9% ) and toxic death in 5 ( 15% ) patients. Although some long lasting complete remissions were seen in head and neck cancer patients treated with this regimen, it appears too toxic to be recommended.

The clinical experience with chemotherapy in mycosis fungoides is practically limited to the action of different types of chemotherapeutic agents on the lesions in far-advanced cases. A large number of agents from almost all classes – alkylating agents, antimetabolites, antibiotics, alkaloids, hormones – have some efficacy in clearing skin lesions. Despite this fact, combination chemotherapy has been the subject of a very small number of publications with conflicting results. The influence on survival, the comparative effects of combination versus single-agent chemotherapy, the value of chemotherapy combined to other treatment modalities have not been submitted to scientific evaluation. Considering the low frequency of the disease and the great variability of the clinical picture, it seems mandatory to implement large cooperative trials, possibly on an international scale.

BRL-4664, a THC analog, has been administered to 23 patients at a dose of 10 or 15 mg repeated twice. All patients were on cisplatin therapy, and 16 of them had experienced severe vomiting during the previous course of cisplatin. There was a statistically significant difference between the group with prior cisplatin therapy and without prior therapy in terms of number of vomiting episodes, emphasizing the role of conditioned reflexes. The dose of 15 mg administered before and twice after the infusion of cisplatin was well tolerated. Only minor side effects were observed.

Carbetimer, a low molecular weight polymer derived from ethylene and maleic anhydride, belongs to a class of chemical compounds different from previously available anticancer agents. It has shown moderate antitumor activity against the Madison 109, Lewis lung, colon 26 and M5076 ovarian carcinomas. In the human tumor stem cell assay, antitumor activity was seen against carcinomas of the breast, ovary, lung, colon and kidney. A total of 26 patients with solid tumors were entered into this trial; carbetimer was given on 5 consecutive days as a 1–2-h intravenous infusion. The dose was escalated from 1.08 to 11 g/m2/day. The drug did not induce the usual side-effects of chemotherapy: leukopenia, thrombocytopenia, alopecia and mucositis were minimal or totally absent. Gastrointestinal toxicity was limited to mild to moderate nausea and vomiting; these were observed at all dose levels and required antiemetics in only two patients. The major side-effects of carbetimer consisted of hypercalcemia and neurotoxicity. Hypercalcemia was dose- and treatment duration-dependent. The precise mechanism of hypercalcemia is presently under investigation, but remains unclear. Neurotoxicity was observed only after prolonged therapy; two patients, who received cumulative doses higher than 250 g/m2, developed a peripheral neuropathy with paresthesia, decrease in sensory perception and motor weakness. One patient recovered completely; the other patient improved slightly before developing fatal brain metastases. Two patients with malignant melanoma exhibited major antitumor response; both were previously treated; after excellent partial responses to carbetimer, both were operated on and one is presently disease-free 2 1/2 years after completion of therapy with carbetimer. In conclusion, carbetimer is a new compound with an unusual pattern of side-effects and interesting antitumor activity against malignant melanoma. Its antitumor activity is presently being investigated in phase II trials.

Ten hyperthermic isolation-perfusions with melphalan were performed for invasive malignant melanoma of the limbs. Four cases at stage II and with in transit metastases (up to 15 cm in diameter) had a complete regression. However, no improvement of survival was noticed: 4 out of 5 stage II patients who died, within 1 year after perfusion, developed a generalized disease. Systemic chemotherapy was administered in 3 patients after perfusion, but they died from distant metastases. The need for an adequate adjuvant treatment added to isolation perfusion is discussed.

Twenty-six adult patients were entered in a phase I trial of carboplatin, a new cisplatin derivative with reduced potential for nephrotoxicity. All patients had solid tumors and the median World Health Organization performance score was 2 (0-3). Twelve patients had not received prior chemotherapy. The drug was administered as a 15-minute IV infusion, without pre- or posthydration, at daily doses of 40-125 mg/m2 for five consecutive days. Antiemetics were given only if needed. Thrombocytopenia and neutropenia were dose related and dose limiting. One patient died from septic shock at the highest dose level. Nonhemolytic anemia was also encountered. Nausea and vomiting were experienced by most patients but gastrointestinal intolerance was severe in only two patients. One patient had hypercreatininemia, which was minor and rapidly reversible. Other toxic effects consisted of negligible fatigue, paresthesia, pruritus, local pain, stomatitis, headache, and alopecia. Although none of the patients achieved a partial or complete response, antitumor effect was strongly suggested in two patients with thyroid and cervix cancer, respectively. Carboplatin is an attractive candidate for phase II trials. In good-risk patients, such trials could be initiated at a daily dose of 100 mg/m2 for five consecutive days every five to six weeks.

One hundred and sixty-two patients with advanced solid tumors were treated with oral dianhydrogalactitol 30 mg/m 2 daily for 10 days every 4–6 weeks . Dose limiting toxicity was hematopoietic. Eight objective responses were seen in 136 evaluable cases. Patients with gastro-intestinal cancer (213 gastric, 13 pancreatic, 223 colorectal) showed objective regressions lasting 1–12 + months . Short lasting partial remissions occurred in 220 lung epidermoid and 118 breast carcinomas. Dianhydrogalactitol has limited chemotherapeutic activity against adult solid tumors but deserves further trial in gastro-intestinal malignancies.

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 40 mg/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 microM (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 microM x hr. 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 microM. The area under the plasma versus concentration time curve for 4'-deoxydoxorubicinol was 0.02 +/- 0.014 microM xhr. 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.

Ametantrone is a new aminoanthraquinone derivative that achieves antitumor activity in a large variety of animal models. It is a dark blue dye. In this phase I study, the drug was given as a 30-min i.v. infusion repeated every 2–3 weeks. Nineteen patients were entered into the trial and received a total of 43 courses. All were adult patients with advanced solid tumors, mainly squamous cell carcinoma of the head and neck and nonsmall cell carcinoma of the lung. Sixteen had undergone prior chemotherapy; only one had not been previously treated. The trial was initiated at a starting dose of 10 g/m2 and dose levels were escalated up to 180 mg/m2. Leukopenia was dose-related, well predictable, rapidly reversible and dose-limiting. At 135 mg/m2, the median WBC nadir was 1800/mm3 (1000–4400) and the median PMN was 950/mm3 (460–2240). Among all courses, WBC nadir occurred on median day 12 (8–18) and recovery was seen on medianday 16 (10–29). Thrombocytopenia (< 100,000/mm3) was encountered in two courses. There was no evidence of cumulative myelosuppression with repeated courses. Non-hematological toxic effects were negligible and included stomatitis in one course, minor alopecia in three patients, and questionably drug-related orthostatic hypotension in three patients. Reversible blue skin discoloration was seen in five patients. All patients treated with ≧ 40 mg/m2 had dark blue urine for 2 or 3 days. Antitumor activity with response 50% could not be documented. Ametantrone appears to be very well tolerated and easy to handle. Its clinical anticancer potential remains to be determined. A dose-schedule of 135 mg/m2 q 2–3 weeks may be recommended for phase II studies in solid tumors.

1,3,5 -Triglycidyl- s -triazinetrione is a triepoxide derivative with attractive antitumor properties in mice. In this phase I trial, the drug was given as an i.v. infusion over 30 + min repeated every 2–3 weeks. The trial was initiated at a starting dose of 33 mg/m 2 and doses were escalated up to 2,000 mg/m 2 . Local thrombophlebitis was dose-limiting and apparently dose-related. Other toxic effects were mild to moderate and consisted of nausea, vomiting, leukopenia and hair loss. More favorable formulations or schedules of administration are needed before testing this new agent in phase II trials.

Resume 1.1. Les auteurs ont etabli le caryotype de 18 malades adultes atteints de leucemie myeloide chronique (LMC). Trente-et-une analyses cytogenetiques ont ete pratiquees. Le chromosome de Philadelphie a ete observe dans tous les cas (dans 12 a100% des mitoses, moyenne 69%), aussi bien lors de la phase chronique que lors de la phase aigue. Le nombre modal etait de 46 chromosomes chez les 13 patients en phase chronique, et chez 6 patients en phase aigue. Une aneuploidie etait presente, lors de la transformation myeloblastique, chez 2 malades. Un troisieme malade avait un nombre modal de 49, quelques semaines avant le deces, sans qu'il y ait de transformation myeloblastique. Ce patient avait une anemie hemolytique et une thrombocytopenie intense. 2.2. Un cas de LMC chez une enfant de 12 ans montrait la presence de 2 chromosomes de Philadelphie dans la majorite des mitoses de la moelle osseuse. 3.3. Un cas de leucemie a polynucleaires neutrophiles avait un caryotype semblable a celui de la LMC, c'est-a-dire avec, comme seule anomalie, la presence du Ph 1 . 4.4. Dans un cas, avec des caracteristiques cliniques et hematologiques semblables a celles de la metaplasie myeloide (anemie, leucocytose moderee, thrombocytemie, evolution de 8 annees sans traitement), le chromosome Ph 1 etait present dans 12% des mitoses. 5.5. La determination semi-quantitative de la phosphatase alcaline dans les granulocytes, selon la methode de Kaplow, a ete pratiquee chez tous les malades, en meme temps que l'analyse cytogenetique. Elle etait tres abaissee chez tous les malades atteints de LMC typique, en phase chronique. Elle etait un peu plus elevee, mais encore inferieure a la normale, chez deux malades en remission. Elle etait normale ou elevee chez 3 malades en transformation myeloblastique. Dans un de ces cas, on notait la presence de 2 chromosomes Ph 1 dans la majorite des cellules. La phosphatase alcaline dans les granulocytes etait aussi tres superieure a la normale dans le cas de LMC de l'enfant, ou 2 chromosomes Ph 1 etaient egalement presents. Elle etait augmentee dans le cas de leucemie a polynucleaires et elle etait presque nulle dans le cas ressemblant a une metaplasie myeloide.

Resume Le chlorhydrate de p-(N′-methyl-hydrazinomethyl)-N-isopropyl-benzamide a ete administrea trente-trois malades atteints de maladie de Hodgkin et a dix-sept malades atteints d'autres lymphomes malins et de leucemies. Un effet objectif certain a ete observe dans vingt-trois cas de maladie de Hodgkin, dans un cas de lymphosarcome, un cas de reticulosarcome, deux cas de leucemie myeloide chronique. Des cas resistants a la radiotheriape, aux agents alkylants, a la prednisolone, etaient sensibles a la methylhydrazine. Une diminution importante des leucocytes a ete observee chez six malades et une thrombocytopenie serieuse chez douze malades. Trois malades sont morts d'infection avec leucopenie. Les autres signes de toxicite etalent des troubles digestifs (vomissements, anorexie, diarrhee), l'alopecie, l'amenorrhee, l'intolerance a l'alcool et une erythrodermie.

The anticancer activity of ametantrone was investigated in a human tumor cloning assay. Tumor samples were freshly obtained from 105 patients. Cells were exposed for 1 hr to drug concentrations of 1 and 10 micrograms/ml. A reduction in the number of tumor colony-forming units by 50% or more was seen in 2/31 breast cancers, 2/25 ovarian cancers, 1/10 primaries of unknown origin, 1/10 melanomas, 2/8 non-small cell lung cancers, 1/5 small cell lung cancers and 1/3 colon cancers. Only three of these in vitro responses were consistently obtained at the probably more relevant concentration of 1 microgram/ml. These findings indicate that low efficacy should be expected in cancer patients with ametantrone. The predictive value of these in vitro phase II data remains to be demonstrated.

Between 1973 and 1977, 84 patients with small cell anaplastic bronchogenic carcinoma underwent staging procedure including brain, liver and bone scan, bone marrow biopsy and peritoneoscopy. Fifty-eight patients with limited disease were treated with concomitant radiation therapy to the primary site and the combination of vincristine and cyclophosphamide (VCR-CPA). Two maintenance chemotherapy schedules were used: methyl CCNU, cyclophosphamide, vincristine and bleomycin (COMB) or VCR-CPA. The median survival was 11 months . No statistical difference could be observed in survival and relapse rates between these two treatments. Twenty-six patients with extensive disease were treated with methyl CCNU, cyclophosphamide, vincristine with or without bleomycin. Median survival was 7 months and the use of bleomycin did not improve the response rate.

The human tumor stem-cell assay was used to investigate the in vitro chemosensitivity of 27 evaluable samples to cisplatin and its analogues, iproplatin and carboplatin, as well as to BCNU, teniposide, vindesine, and dibromodulcitol. All agents exhibited some antitumor activity with the exception of dibromodulcitol (zero response out of 19 evaluable samples). Vindesine, BCNU, and carboplatin were the three most active compounds, with response rates of 29%, 23%, and 22%, respectively. There was a lack of complete cross-resistance between carboplatin and cisplatin as well as between carboplatin and BCNU. Our data suggest that clinical studies with carboplatin and combinations of vindesine plus cisplatin and its analogues may be worthwhile.

In a series of 45 patients with small cell anaplastic carcinoma of the lung with disease limited to one hemithorax, 15 of them presented at the time of diagnosis a superior vena cava syndrome. Both groups were similar in terms of response rate and survival. Superior vena cava syndrome is not an independent prognostic factor in small cell carcinoma of the lung.

The effect of 3 anthracene derivatives, mitoxantrone, ametantrone, bisantrene, on 4 normal human bone marrows, was studied using the myeloid stem cell assay developed by Pike and Robinson, in order to define to what extent this test could be used to predict the relative clinical hematologic toxicity of new anticancer agents. For the 3 drugs, an exponential relationship between colony survival and drug concentration was found, but was much steeper for mitoxantrone (slope = -195.2 +/- 8.8/micrograms/ml) than for ametantrone (slope = 5.1 +/- 1.0/micrograms/ml, p less than or equal to 0.001) and bisantrene (slope = 7.1 +/- 0.3/micrograms/ml, p less than or equal to 0.001). The difference of slope between ametantrone and bisantrene was of borderline significance (p less than or equal to 0.05). The ratios of concentrations inducing a 50% growth inhibition for mitoxantrone versus bisantrene and for ametantrone versus bisantrene were close to the corresponding ratios of concentrations inducing a 90% growth inhibition. The relative in vitro toxicities reproduce very well the relative myelosuppression observed in clinical trials with mitoxantrone versus bisantrene but the results were less satisfactory for the comparison of these 2 agents with ametantrone. In addition, our data suggest that, for these 3 compounds, intrinsic myeloid progenitor sensitivity is a major determinant of leukopenia.

Eighteen adult patients with solid tumors were treated with oral menogaril, a new anthracycline antibiotic active against human breast cancer after intravenous administration. The drug was given orally on 3 consecutive days every 4 weeks at doses ranging from 50 to 175 mg/m2/day. Reversible and dose-related leukopenia was the dose-limiting toxicity. Thrombocytopenia was less frequent. Hematologic toxicity was maximal usually 2 weeks after treatment and recovery usually occurred within 4 weeks. At doses from 50 to 150 mg/m2/day, non-hematologic side-effects of oral menogaril were infrequent and mild and consisted of nausea and vomiting (one patient), alopecia (two patients), mucositis (two patients) and liver function test abnormalities (three patients). The single patient treated at a daily dose of 175 mg/m2/day developed grade IV leucothrombocytopenia, with fever and gastrointestinal bleeding. This was followed by heart failure and the patient died from multisystem organ failure. Peak plasma concentrations of menogaril ranged from 0.043 to 0.409 microM and were linearly correlated with the dose. Similarly, the area under the plasma concentration versus time curve varied from 0.33 to 9.59 microM X h and was linearly correlated with the dose. The mean harmonic half-life was 11.3 +/- 6.4 h. A comparison of the data from the present trial and our previous study with intravenous menogaril indicates a bioavailability of 32 +/- 12%. There was an excellent relationship between the white blood cell decrease (as a percentage of the pretreatment value) and several pharmacokinetic parameters; the best correlation was obtained with the plasma concentration of menogaril at 4 h after treatment. A dose of 150 mg/m2/day for 3 consecutive days is recommended for phase II trials with oral menogaril but the bioavailability of the drug should be monitored carefully and, more specifically, the concept of a pharmacokinetic adjustment of the dose of menogaril should be evaluated prospectively.

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.