Increase In Median Lifespan Research Articles

The response of mouse lung tumors to combinations of CCNU and misonidazole

The effect of combining the radiosensitizer misonidazole (MISO) and the chemotherapeutic agent 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) on mouse lung tumors of different sizes and hypoxic fractions was tested. KHT sarcoma lung colonies were treated at volumes of ∼0.7 and 2.0 mm 3. At these sizes the lung colonies contained ∼5 and 15% hypoxic tumor cells respectively. For the smaller lung colonies response to CCNU or the CCNU-MISO combination was evaluated by determining the percent of mice tumor-free 100 days after treatment. This assay could not be used when 2.0 mm 3 lung colony bearing mice were treated, since at this size only a few animals could be cured with either the single or combined modality therapy. Consequently, tumor response in these experiments was assessed using an increase in lifespan assay or a tumor growth delay assay. When 0.7 mm 3 KHT lung colonies were treated with CCNU plus 1.0 mg/g MISO, the TCD 50 100 (dose to cure 50% of the mice of their tumors in 100 days) was reduced by a factor of 1.5–1.8 compared to mice receiving only CCNU. However, because the single agent therapy was less toxic than the combination, increasing doses of CCNU ultimately resulted in the same level of cure as could be achieved with the CCNU-MISO combination. In the 2.0 mm 3 lung colonies studies, however, when compared at the maximally tolerated doses, the addition of 0.5 or 1.0 mg/g MISO to CCNU led to a percent increase in median lifespan, which was a factor of 1.4–1.5 greater than could be achieved with CCNU alone. This increase in lifespan was shown, using growth delay studies, to be a direct consequence of an enhanced tumoricidal response to the combination therapy. These findings indicate that in this lung tumor model an improved therapeutic result may be achieved through the addition of MISO to treatment with CCNU.

Effect of concurrent calcium leucovorin infusion on 5-fluorouracil cytotoxicity against murine L1210 leukemia.

We examined the effect of concurrent SC infusion of calcium leucovorin (LV) on the action of 5-fluorouracil (FUra) against mouse L1210 leukemia implanted either SC or IP. Mice bearing the SC tumor treated with FUra (100 mg/kg, IP, day 1) plus infusion with either LV (11.5 mg . kg-1 . day-1, days 1-4), or 0.9% NaCl (days 1-4) resulted in an identical increase in median lifespan (ILS) of 28%. Similar experiments with FUra (100 mg/kg) plus LV infusion (115 mg . kg-1 . day-1) or FUra (200 mg/kg) plus LV infusion (115 mg . kg-1 . day-1) resulted in 50% and 59% ILS, respectively, which were not different from that obtained with the same doses of FUra plus 0.9% NaCl infusion. Mice bearing the IP tumor treated with FUra (100 mg/kg, IP, day 1) plus infusion with either LV (11.5 mg . kg-1 . day-1, days 1-4) or 0.9% NaCl (days 1-4) had an identical 56% ILS. Similar experiments with FUra (100 mg/kg) plus LV infusion (115 mg . kg-1 . day-1) or FUra (200 mg/kg) plus LV infusion (115 mg . kg-1 . day-1) resulted in 67% and 94% ILS, respectively, which were not different from those obtained with the same doses of FUra plus 0.9% NaCl infusion. Treatment of normal mice with FUra (200 mg/kg, IP, day 0) plus LV infusion (115 mg . kg-1 . day-1, days 0-3) was no more toxic than FUra plus 0.9% NaCl infusion, judging by similar transient decreases in body weight and no mortality. The data indicate that concurrent infusion with the LV failed to enhance the action of FUra against the mouse L1210 leukemia.

ChemInform Abstract: ANTITUMOR AGENTS. 1. 1,4‐BIS((AMINOALKYL)AMINO)‐9,10‐ANTHRACENEDIONES

AbstractDurch Kondensation der Verbindungen (I) und (IV) mit den Aminen (II) und (V) erhält man die Vertreter (III) und (VI), von denen letzterer zu (VII) aromatisiert wird.

An analysis of dose-effect relationship in the radiotherapy of malignant gliomas

The relationship between increasing survival and increasing doses of radiotherapy has been examined in 621 patients who were entered into three successive Brain Tumor Study Group protocols between 1966 and 1975. These patients were operated upon and had histologically proven malignant gliomas. The median survival of patients who received no radiotherapy was 18.0 weeks; for those who had ⪯4500 rad, it was 13.5 weeks (p = .346); those who received 5000 rad had a median survival of 28 weeks (p < .001), 5500 rad - 36.0 weeks (p < .001), and 6000 rad - 42.0 weeks (p < .001). The specific relationship between 5000 and 6000 rad indicates a 1.3 times increase in median life span associated with the higher dose (p = .004). A detailed analysis of specific factors which might have significantly biased results indicated that patients who received less than 4500 rad were not comparable to other groups of patients because they had a poorer initial performance status and a greater number died before completion of radiotherapy. Factors of importance including parameters of radiotherapy, pathology distribution, the influence of corticosteroids, and the effect of age, sex, and initial performance status were all comparable within the various other subgroups. No other treatment characteristics or selective factors which might have a direct effect on survival were identified. It was concluded that radiotherapy had a significant influence on the survival of patients with malignant glioma and that a clear-cut dose-effect relationship exists.

Antitumor agents. 1. 1,4-Bis[(aminoalkyl)amino]-9,10-anthracenediones.

The condensation of alkylenediamines with quinizarin or with 2,3-dihydro-1,4,5,8-tetrahydroxy-9,10-anthracenedione, followed by oxidation, gave 1,4-bis[aminoalkyl)amino]-9,10-anthracenediones. Some of these compounds and their 2,3-dihydro derivatives were markedly active against both leukemias and solid tumors in mice. Activity was maximal with 5,8-dihydroxylation and 1,4-bis[(2-aminoethyl)amino] substitution, in which the terminal nitrogen atoms were either unsubstituted (compound 50) or carried 2-hydroxyethyl groups (compound 40), indicating the importance of hydrophilicity. Against B-16 melanoma, 50 gave greater than 433% increase in median life span (ILS) with 7/10 80-day survivors. Against P-388 leukemia, 40 gave greater than 500% ILS with 4/5.60-day survivors; its efficacy and therapeutic index equaled or surpassed those of adriamycin, cyclophosphamide, daunorubicin, methotrexate, or 5-fluorouracil. Against L-1210 leukemia, B-16 melanoma, and colon tumor 26, 40 was generally as effective or more effective than adriamycin and is now undergoing preclinical toxicological evaluation.