The serial cultivation of human diploid cell strains.

Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors

The median-effect equation derived from the mass-action law principle at equilibrium-steady state via mathematical induction and deduction for different reaction sequences and mechanisms and different types of inhibition has been shown to be the unified theory for the Michaelis-Menten equation, Hill equation, Henderson-Hasselbalch equation, and Scatchard equation. It is shown that dose and effect are interchangeable via defined parameters. This general equation for the single drug effect has been extended to the multiple drug effect equation for n drugs. These equations provide the theoretical basis for the combination index (CI)-isobologram equation that allows quantitative determination of drug interactions, where CI 1 indicate synergism, additive effect, and antagonism, respectively. Based on these algorithms, computer software has been developed to allow automated simulation of synergism and antagonism at all dose or effect levels. It displays the dose-effect curve, median-effect plot, combination index plot, isobologram, dose-reduction index plot, and polygonogram for in vitro or in vivo studies. This theoretical development, experimental design, and computerized data analysis have facilitated dose-effect analysis for single drug evaluation or carcinogen and radiation risk assessment, as well as for drug or other entity combinations in a vast field of disciplines of biomedical sciences. In this review, selected examples of applications are given, and step-by-step examples of experimental designs and real data analysis are also illustrated. The merging of the mass-action law principle with mathematical induction-deduction has been proven to be a unique and effective scientific method for general theory development. The median-effect principle and its mass-action law based computer software are gaining increased applications in biomedical sciences, from how to effectively evaluate a single compound or entity to how to beneficially use multiple drugs or modalities in combination therapies.

http://www.protocol-online.org/forums/uploads/monthly_09_2010/post-8165-008503000%201284677034.ipb

Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies

A controlled, prospective, randomized study evaluated the use of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and/or radiotherapy in the treatment of patients who were operated on and had histological confirmation of anaplastic glioma. A total of 303 patients were randomized into this study, of whom 222 (73%) were within the Valid Study Group (VSG), having met the protocol criteria of neuropathology, corticosteroid control, and therapeutic approach. Patients were divided into four random groups, and received BCNU (80 mg/sq m/day on 3 successive days every 6 to 8 weeks), and/or radiotherapy (5000 to 6000 rads to the whole brain through bilateral opposing ports), or best conventional care but no chemotherapy or radiotherapy. Analysis was performed on all patients who received any amount of therapy (VSG) and on the Adequately Treated Group (ATG), who had received 5000 or more rads radiotherapy, two or more courses of chemotherapy, and had a minimum survival of 8 or more weeks (the interval that would have been required to have received either the radiotherapy or chemotherapy). Median survival of patients in the VSG was, best conventional care: 14 weeks (ATG: 17.0 weeks); BCNU: 18.5 weeks (ATG: 25.0 weeks); radiotherapy: 35 weeks (ATG: 37.5 weeks); and BCNU plus radiotherapy: 34.5 weeks (ATG: 40.5 weeks). All therapeutic modalities showed some statistical superiority compared to best conventional care. There was no significant difference between the four groups in relation to age distribution, sex, location of tumor, diagnosis, tumor characteristics, signs or symptoms, or the amount of corticosteroid used. An analysis of prognostic factors indicates that the initial performance status (Karnofsky rating), age, the use of only a surgical biopsy, parietal location, the presence of seizures, or the involvement of cranial nerves II, III, IV, and VI are all of significance. Toxicity included acceptable, reversible thrombocytopenia and leukopenia.

Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: A cooperative clinical trial

In recent years attention has been increasingly turning to the cell surface as the seat of an impor tant part of the malignant transformation. This widening of the field of interest of cancer workers owes its beginning largely to the work of Coman (34). Coman was concerned with how invasion and metastasis occur, and this crucial aspect of the cancer problemâ€”crucial in the sense that it con cerns the difference between benign and malignant growth-â€”must still be the main preoccupation of a review on the cell surface in relation to cancer. Other aspects may, however, be linked together in a speculative way, and to these we will refer brief ly. The review is divided into two main sections: (a) a discussion of the biological evidence for the existence of surface peculiarities of malignant cells (M.A. has been responsible for this section) ; (6) a discussion of the physical evidence as to what the surface peculiarities may be (E.J.A. has been re sponsible for this section).

https://cancerres.aacrjournals.org/content/canres/22/5_Part_1/525.full.pdf

The surface properties of cancer cells: a review.

Mice with early or advanced leukemia L1210 were treated with the inorganic antitumor agent, cis -platinum(II) diamminodichloride [ cis -Pt(II)], alone or combined wi

The enhanced therapeutic effect of cis-platinum (II) diamminodichloride against L1210 leukemia when combined with cyclophosphamide or 1,2-bis(3,5-dioxopiperazine-1-yl)propane or several other antitumor agents.

The effect of phenobarbital or 2-diethylaminoethyl-2,2-diphenylvalerate (SKF 525A) on the activation of cyclophosphamide in mice was examined. Cyclophosphamide was injected into BDF1 male mice pretreated with phenobarbital or SKF 525A at various time intervals before and simultaneously with implantation of leukemia L1210 cells. The mean survival times were used as the parameter to study the retention of the antileukemic activity of the drug. In a parallel experiment with a chemical procedure the quantity of the alkylating metabolites of cyclophosphamide in plasma was determined at various time intervals after cyclophosphamide administration. The results of the chemical experiments showed that pretreatment with phenobarbital accelerated the production of alkylating metabolites of cyclophosphamide followed by a rapid depletion of the alkylating drug. Pretreatment with SKF 525A retarded the activation process which resulted in the slow release of the drug over a longer period of time. The biological experiments indicated that the duration of antileukemic activity was shortened by phenobarbital and lengthened by SKF 525A. The similarity of the results of the biological and chemical studies relating to the effect of pretreatment on the metabolism of cyclophosphamide suggests that the metabolites of cyclophosphamide measured by the chemical assay are responsible for the antileukemic activity. The chemical data show that pretreatment with SKF 525A increased and pretreatment with phenobarbital decreased the total amount of alkylating metabolites. In studying combination chemotherapy with drugs that influence cyclophosphamide activation, the chemical and biological procedures reported here are useful tools in evaluating the effects of these drugs on cyclophosphamide therapy.

The effect of phenobarbital or 2-diethylaminoethyl-2,2-diphenylvalerate on the activation of cyclophosphamide in vivo

Summary In treatment of leukemia (L1210), cytosine arabinoside (ara-C) was more effective in the early stage of leukemia (L1210) than when the treatment was started in the advanced stage of the diseases in mice. Multiple treatment with ara-C resulted in a marked increase in the life span of mice with early and advanced leukemia. The antileukemic effects of ara-C were nearly comparable in the several multiple schedules of treatment employed in this study except when the interval between treatments was increased to 7 days. In each instance the response achieved with ara-C was notably greater than that observed with a daily optimal dose of amethopterin. A single injection was appreciably less effective against the early and late disease. Similarly, daily therapy limited to 3 or 5 days against advanced leukemia failed to produce extensive increases in the survival time. In studies with normal and leukemic mice, the narrow therapeutic margin of safety of ara-C was evident. The optimal treatment doses for the leukemic mice were generally close to the toxic dose for the normal mice.

https://cancerres.aacrjournals.org/content/canres/26/5/853.full.pdf

Chemotherapy of leukemia L1210 in mice with 1-beta-d-arabinofuranosylcytosine hydrochloride. I. Influence of treatment schedules.

https://science.sciencemag.org/content/sci/123/3195/502.2.full.pdf

Transformation of normal human fibroblasts into histologically malignant tissue in vitro.

Summary Enchanced therapeutic effectiveness has been demonstrated by combining methotrexate and 5-fluorouracil in the treatment of murine leukemia L1210 Optimal combinations of the 2 drugs consistently showed greater antileukemic activity than optimal treatment with each drug by itself The treatment schedules resulting in this enhanced activity were characterized by relatively low and therapeutically ineffective doses of 5-fluorouracil, whereas the associated level of methotrexate ranged from slightly less than optimal to optimal The therapeutic activity of the combination of the drugs was limited by the development of host toxicity similar to that observed when the drugs were used by themselves

/pdf/the-antileukemic-effectiveness-of-5-fluorouracil-and-3o0l3k8l1t.pdf

Ira Kline

Papers

The enhanced therapeutic effect of cis-platinum (II) diamminodichloride against L1210 leukemia when combined with cyclophosphamide or 1,2-bis(3,5-dioxopiperazine-1-yl)propane or several other antitumor agents.

The effect of phenobarbital or 2-diethylaminoethyl-2,2-diphenylvalerate on the activation of cyclophosphamide in vivo

Chemotherapy of leukemia L1210 in mice with 1-beta-d-arabinofuranosylcytosine hydrochloride. I. Influence of treatment schedules.

Transformation of normal human fibroblasts into histologically malignant tissue in vitro.

The Antileukemic Effectiveness of 5-Fluorouracil and Methotrexate in the Combination Chemotherapy of Advanced Leukemia L1210 in Mice