Henri Tagnon

R17934-NSC 238159: A new antitumor drug—I. Effect on experimental tumors and factors influencing effectiveness

Abstract R 17934 -NSC 238159 : methyl[ 5 -( 2 -thienyl carbonyl)- 1 H-benzimidazol- 2 yl] carbamate, a new antitumor agent was found active against lymphoid L 1210 leukemia, lymphocytic P 388 leukemia, melanotic melanoma B 16 and Lewis Lung carcinoma. This activity was influenced by the vehicle used in the preparation of the suspension and the route of administration of the drug, and to a lesser extent by the schedule of administration. The low toxicity of therapeutically active doses singles out this compound for possible clinical application.

Comparison of adriamycin with DNA-adriamycin complex in chemotherapy of experimental tumors and metastases

Abstract The effects of adriamycin and of two different preparations of DNA-adriamycin complex were compared in mice on the following experimental tumors: leukemia L 1210 , melanotic melanoma B 16 and Lewis Lung carcinoma. Plasma levels were determined in different strains of mice: DBA/ 2 , CDF 1 and BDF 1 , bearing L 1210T leukemia (blood form). Increased therapeutic effectiveness was observed with the complex (prepared with Dr. Trouets method) in DBA/ 2 mice bearing L 1210T leukemia (blood form) treated i.v. and in BDF 1 mice bearing melanoma B 16 i.p. treated i.p. On the other hand, adriamycin alone, when given i.v., was more effective than the complex on primary solid tumors, including leukemia L 1210T in solid form. Therefore, on leukemia L 1210T , the Trouet complex preparation was more effective than adriamycin alone on the leukemic form, while adriamycin alone was more effective on the solid form. The therapeutic effect of the DNA-adriamycin (Trouet preparation) and adriamycin alone given i.v. was found to be similar on the formation of lymph node metastases in DBA/ 2 mice bearing L 1210 s.c. inoculated i.v. and lung metastases in BDF 1 mice bearing Lewis Lung carcinoma i.m. treated i.v. The disappearance of adriamycin from the plamsa of DBA/ 2 mice after treatment with the DNA-adriamycin complex is slower than the disappearance of the drug after a treatment with adriamycin alone. The therapeutic action of DNA-adriamycin seems to require direct contact between the complex and the tumor cells. This is achieved by local injection in the case of solid tumors and by i.v. injection in the case of leukemia.

Comparison of adriamycin with the dna-adriamycin complex in chemotherapy of l1210 leukemia.

Abstract The effect of adriamycin and a complex DNA-adriamycin was compared in normal mice and in mice with leukemia L 1210 . The DNA-adriamycin was found to be less toxic than adriamycin, especially during the first few days of administration. Increased therapeutic effectiveness was observed in one type of leukemia L 1210 which was obtained from another laboratory and has a better prognosis than the L 1210 maintained in our laboratory and on which no therapeutic enhancement of the DNA-adriamycin complex was demonstrated. The incidental finding that L 1210 leukemia from different strains and laboratories may show different responses to the same treatment invites precaution in the interpretation of comparative studies with this model.

R17934 NSC238159: A new antitumor drug. II. Effect on mitotic cycle of L1210 leukemia cells in vivo and synergism with cytosine arabinoside (NSC 63878)

Abstract R 17934 methyl [ 5-2 -thienyl carbonyl)- 1 H benzimidazol- 2 -yl] carbamate an antitumor agent effective against L 1210 and several other experimental tumors was observed to produce arrest of mitosis in metaphase of L 1210 leukemia cells in vivo in a way very similar to vincristine. In combination with cytosine arabinoside, therapeutic synergism was observed when cytosine arabinoside was administered 15 or 24 hr after R 17934 . In contrast, treatment with cytosine arabinoside given immediately after R 17934 was found to result in an antagonistic combination. Combined treatment with cytosine arabinoside preceding the administration of R 17934 by 15–24 hr also demonstrated a synergistic effect. This synergism was less pronounced in early leukemia than when R 17934 was given 15–24 hr before cytosine arabinoside but equally pronounced in the case of advanced leukemia. Maintained synergism after inverting the order of drug administration is not in agreement with the explanation invoked for this synergism based on prior metaphase induction followed by the administration of a metaphase active drug.

The antitumoral activity of some derivatives of 6-aminochrysene

Abstract Twenty-two N-substituted derivatives of the carcinostatic 6-aminochrysene have been tested as potential carcinostatic agents (using 6-aminochrysene as a standard) on spontaneous mammary tumor in [C3H/020] F1 mice, and on the slow-growing transplanted rhabdomyosarcoma in inbred WAG/Rij rats. Many of these compounds displayed important activity against both types of tumor, and some of them merit further investigations. In contrast compounds active on these experimental tumors, were completely inactive on Ehrlich carcinoma and on Sarcoma 180.

Characterization of two direct fibrinogenolytic activities and of one proteolytic inhibitor activity in the human prostate

Abstract The gel filtration of a fraction prepared by precipitation of a crude extract of human benign hyperplastic prostate tissue resulted in two separated peaks of direct proteolytic activity (DPA1 and DPA2) devoid of any kinase or plasminogen activator activity. A third peak showing proteolytic inhibitory activity (PIf) was also obtained. DPA1 was active on fibrinogen as well as on casein, although the proteolysis of fibrinogen was limited as shown by the electrophoretic pattern of breakdown products. This peak had an esterase activity on p-tosyl-Larginine methyl ester (TAME) but not on L-lysine methyl ester (LME). DPA2 was devoid of esterase activity and was much more active on fibrinogen than on casein, releasing large fragments of fibrinogen. DPA1 and DPA2 appeared to be different from plasmin, to have an active serine center and not to be dependent on thiol groups for their activity. Their possible role in the pathogenesis of the hemorrhagic diathesis associated with some prostatic disorders should be envisaged. Although the human prostate crude extract contained an antiplasmin and an antitrypsin activity, PIf was ineffective against plasmin and did not inhibit either one of the two DPAs. PIf had identical antigenic determinants as plasma α 1 -antitrypsin

The Role of Hormones in the Modern Treatment of Advanced Breast Cancer

In this chapter an attempt will be made to define the significance and role of hormonal treatment of breast cancer. This type of treatment can no longer be used alone and it should be considered in the general perspective of a resolute attempt to utilize all existing biological and pharmacologic information available for the improvement of patient care. This is not a complete review of the subject but rather a chapter in the nomenclature and critical evaluation of methods of treatment now available to a “task force” with ambitious therapeutic aims. Recent progress in the treatment of Hodgkin’s disease, leukemia, osteogenic sarcoma, and of other tumor types has provided the encouragement for a renewed and concerted attack on breast cancer, a disease which affects 1 out of every 20 women and has a mortality rate of probably over 75% which has practically remained unchanged in the last 50 years.

Analysis of the Androgen Binding in Human Benign Prostatic Hypertrophy

In order to delineate optimal conditions for the determination of androgen specific binding in human benign prostatic hypertrophy tissues (BPH), extracts of these tissues were prepared using buffers of different compositions. The binding of 5 alpha-dihydrotestosterone (DHT) and of methyltrienolone (R 1881) was analyzed using agar gel electrophoresis. This method allowed the detection of 3 different high affinity tissular binding peaks with similar specificity. Moreover, the inhibition by each of the competitors was also the same for both ligands. It could be demonstrated that none of the observed peaks resulted from the binding of 1 of the ligands to sex hormone binding globulin (SHBG) or to a progesterone receptor. Hypotheses about the possible origin of these peaks are discussed.

Ein vergleichender Überblick zur Kombinationstherapie: Zwei β-Laktame versus β-Laktam plus Aminoglykosid

We have reviewed the available literature on the controlled use of combinations of beta-lactams in the treatment of fever in neutropenic patients, as compared to that of combinations of beta-lactams and aminoglycosides. We compared overall responses, responses in septicemia and various other infections, according to different pathogens and degree of neutropenia, and we evaluated toxicity. Overall, these results showed that response rates with combinations of two beta-lactams are similar to those obtained with combinations of a beta-lactam and an aminoglycoside for infections in immunocompromised patients with serious underlying diseases. They also suggest that the emergence of resistance of pathogens to beta-lactams has often been coped by the use of newer drugs in infections caused by Enterobacteriaceae, but much less effectively in the case of Pseudomonas aeruginosa infections. There are still other important theoretical reasons for preferring an aminoglycoside-containing combination for empiric therapy in febrile neutropenic patients, and our overall conclusion is that a large-scale study comparing beta-lactam combinations to the traditional beta-lactam plus aminoglycoside regimens is mandatory.ZusammenfassungDie vorliegende Arbeit ist ein zusammenfassender Bericht über publizierte kontrollierte Studien zur Behandlung von Fieberzuständen bei neutropenischen Patienten mit Doppel-β-Laktam-Kombination im Vergleich zu β-Laktam/Aminoglykosid-Kombination. Wir stellten die Gesamtansprechrate gegenüber, sowie die Ansprechrate bei Septikämie und verschiedenen anderen Infektionen, entsprechend den beteiligten Erregern und dem Grad der Neutropenie und werteten die Daten zur Toxizität aus. Insgesamt waren die Ansprechraten bei Kombinationen aus zwei Laktamen mit Kombinationen eines Laktams und eines Aminoglykosids bei Infektionen bei Patienten mit schweren Grunderkrankungen und eingeschränkter Immunabwehr ähnlich. Darüber hinaus zeigen die Ergebnisse auch, daß die Resistenzentwicklung der Erreger gegenüber β-Laktam-Antibiotika zwar bei den Enterobacteriaceae durch den Einsatz neuer Substanzen gut beherrscht werden konnte, nicht aber beiPseudomonas aeruginosa. Zudem bestehen noch weitere wichtige theoretische Gründe, in der empirischen Therapie febriler Zustände bei neutropenischen Patienten einer Aminoglykosid-haltigen Kombination den Vorzug zu geben. Unsere Schlußfolgerung ist, daß eine groß angelegte Studie zum Vergleich von Doppel-β-Laktam-Kombination mit der traditionellen β-Laktam-/Aminoglykosid-Kombination durchaus angezeigt wäre.SummaryWe have reviewed the available literature on the controlled use of combinations of betalactams in the treatment of fever in neutropenic patients, as compared to that of combinations of beta-lactams and aminoglycosides. We compared overall responses, responses in septicemia and various other infections, according to different pathogens and degree of neutropenia, and we evaluated toxicity. Overall, these results showed that response rates with combinations of two β-lactams are similar to those obtained with combinations of a beta-lactam and an aminoglycoside for infections in immunocompromised patients with serious underlying diseases. They also suggest that the emergence of resistance of pathogens to β-lactams has often been coped by the use of newer drugs in infections caused by Enterobacteriaceae, but much less effectively in the case ofPseudomonas aeruginosa infections. There are still other important theoretical reasons for preferring an aminoglycoside-containing combination for empiric therapy in febrile neutropenic patients, and our overall conclusion is that a large-scale study comparing β-lactam combinations to the traditional β-lactam plus aminoglycoside regimens is mandatory.

Combination chemotherapy with AMSA on L1210 leukaemia and B16 melanoma

Abstract Clinical interest in AMSA, [ 4′-9 (acridinylamino)methanesulfon- m -anisididel has grown recently because it has shown remarkable activity in the treatment of adult myelogenous acute leukaemia. In the present investigation on two experimental murine tumours, namely L 1210 leukaemia and B 16 melanoma, m-AMSA was administered in association with BCNU, melphalan (MLP) and DTIC. The therapeutic activity of the AMSA-MLP-BCNU combination in murine L 1210 leukaemia was compared to that of the MLPBCNU-DTIC combination. These two associations proved to be very active ( 30 % cures were recorded on day 60 ). The dose levels of the drugs used in the combination represent only 30–50 % of the optimal dose of the same drugs given separately. When DTIC was added to the AMSA-MLP-BCNU combination, considerable lengthening of survival time as well as up to 7 cures out of 10 mice on day 60 were recorded. However, none of the combination chemotherapy was able to induce 10 cures (out of 10 mice) like treatment with BCNU, at optimal dose.