Specific biochemical molecules used as potential biologic markers, including modified nucleosides, polyamines, and pyrimidine catabolic end-products, were quantitatively measured in the urine of seven patients with Burkitt's lymphoma before, during, and after one or more courses of therapy. The results of this preliminary study demonstrated that patients with this disease frequently excrete significantly increased amounts oof modified nuceleosides (considered to be derived primarily from transfer ribonucleic acid), polyamines, and beta-aminoisobutyric acid during the course of their disease. With successful treatment and rapid destruction of tumor cells, a concomitant rise in these molecules occurs. Elevations were observed prior to chemotherapy and changes in levels associated with treatment or tumor progression appeared to correlate with disease status and to aid in assessing antitumor response. Periodic follow-up analysis of these molecules may be helfful in appraising relapse or recurrence of the malignancy prior to overt evidence of tumor by existing clincial means.
A highly sensitive and specific rapid assay for 5-fluorouracil (5-FU) in plasma samples at concentrations as low as 1 ng/ml was developed using mass fragmentography. Highly enriched C14-5-FU was empolyed as an internal standard. A two-compartmental open model for the disposition of free 5-FU in plasma is proposed. The beta-phase of 5-FU plasma elimination describes the pool size of anabolic metabolites, assuming this model is correct. Injections of 5-fu at 15, 40, and 90 mg/kg in rats resulted in an alpha-phase of elimination from plasma with a half-life of 10-18 minutes. The beta-phase could only be measured after the injection of 90 mg/kg of 5-FU and amounted to about 20 hours in two rats. Higher doses resulted in an unproportional increase in 5-FU plasma concentrations in the beta-phase, thus establishing nonlinear kinetics, presumably of the degradative metabolism. Plasma concentrations of 5-FU in man were measured after oral and intravenous administration of 15 mg/kg of 5-FU. Plasma elimination half-lives after intravenous doses were 12 minutes and dropped below measurable levels 2 hours after administration in three patients. After oral administration, peak plasma levels of 5-FU varied between 0.8 and 60 mug/ml of 5-FU in three patients after 10 minutes to 2 hours. Two of these patients showed rapid absorption and a measurable beta-phase of 5-FU plasma elimination possibly indicating a larger anabolic pool size of 5-FU-derived nucleosides and nucleotides when compared to patients receiving intravenous doses. This study may provide a pharmacokinetic rationale to monitor patients receiving 5-FU treatment.
An initial clinical phase I trial of isophosphamide has been carried out at dose levels of 200-10,000 mg/m2 of body surface area using a single-dose, every-3-week schedule. Significant toxicity was not seen at isophosphamide dose levels less than 2900 mg/m2. At higher doses, nausea and vomiting was nearly universal. Hematologic toxicity manifested by leukopenia occurred in 12 of 20 patients treated with doses of 3800-7000 mg/m2. Thrombocytopenia to 100,000 platelets/mm3 was not seen in any patient. Urinary bladder toxicity manifested by hemorrhagic cystitis was seen in 15 of 23 patients treated with doses of 3800-10,000 mg/m2. Hemorrhagic cystitis could be completely prevented by bladder irrigation with N-acetyl-L-cysteine (1% solution, 2000 ml/day). With careful attention to hydration, renal toxicity was largely prevented with blood urea nitrogen elevations to 30 mg/dl in only two of 14 patients receiving isophosphamide doses of 5000-7000 mg/m2. Another side effect was central nervous system toxicity in seven of 17 patients at doses of 5000-10,000 mg/m2. For phase II trials a dose of 5000 mg/m2 is recommended, with careful attention to the state of hydration in the patient and with the knowledge that bladder irrigation may be necessary for the prevention and/or amelioration of bladder toxicity.
The effectiveness of cis-dichlorodiammineplatinum(II) in the treatment of human malignancies is evaluated. The first stage of our investigation consisted of a phase I study to determine toxicity. In the second stage attempts were made to reduce toxicity by varying the modes of administration, and the third stage comprised studies of combination chemotherapy including cis-dichlorodiammineplatinum(II). A total of 74 patients have been treated, 20 of whom received the combination of cis-dichlorodiammineplatinum(II) and cyclophosphamide. Major toxic effects included vomiting, mild leukopenia and thrombocytopenia, decreased creatinine clearance, audiologic toxic effects, hyperuricemia, and nephrotoxicity. Measurable regression of tumors was seen in 18 of the 74 patients and ten of the 18 patients who responded had been given the combination of cis-dichlorodiammineplatinum(ii) and cyclophosphamide.
A comparison has been made of the effects of three nitrosoureas (BCNU, CCNU, and methyl-CCNU) on the cells of Lewis lung carcinoma and B16 melanoma in vivo using a new in vitro method for assaying colony-forming cells. In addition, the effect on early hemopoietic precursors has been studied using the in vivo spleen colony assay and the in vitro agar colony assay. The results show that the three nitrosoureas are selective against Lewis lung carcinoma and B16 melanoma relative to normal hemopoietic precursors. Furthermore, the effect of these nitrosoureas is unchanged when the rate of proliferation of the hemopoietic precursor cells is increased.
A computer-based model of the pharmacokinetics of cytosine arabinoside (ara-C) and its active metabolite, ara-CTP, has been developed. This model, which is an intracellular extension of the Bischoff-Dedrick model of multi-organ pharmcokinetics gives predictions which are in agreement with the recent measurements of Chou et al on tissue concentrations of ara-CTP and Borsa et al on blood levels of ara-C. It is shown that the ara-CTP halving time in tissue is much greater than the ara-C halving time in blood because of low tissue levels of phosphatase. For a single dose at the LD10 level in mice, significant splenic DNA inhibition is calculated to occur for 26 hours, while the ara-C levels are negligible in 6 hours. The calculated duration of cytostatic effect at lower dosages (2.5 mg/kg) is 10 or 12 hours, while ara-C blood levels are negligible within 3 hours. Implications for cell kinetics and scheduling studies are also briefly described.
Twenty-seven unselected patients with limited disease non-oat-cell bronchogenic carcinoma were treated with a chemotherapy- radiotherapy protocol which consisted of bleomycin, vincristine, and methotrexate followed by split-course radiation. There were 15 objective responders with a median survival time in excess of 70+ weeks in contrast to a median survival time of 26 weeks for nonresponders (P less than 0.01). Objective benefit was limited to the epidermoid carcinoma group since none of the adenocarcinoma group achieved a greater than 50% reduction in maximum tumor diameter. The median survival time for the entire groups was 42 weeks in contrast to a recent split-course radiotherapy historical control group whose median survival time was 38 weeks. Toxic effects were predominantly gastrointestinal.
The purpose of this paper is to document the procedures needed to construct pharmacokinetic models based on physiologic, physicochemical, and pharmacologic principles. Extensive descriptions of the basic ideas are provided, along with the corresponding equations. The notions of scaling between various animal species will be described and examples will be given. The important factors determining the choice and number of compartments are based on the properties of the drug and the desired purposes of the pharmacokinetic model. The important concept of flow-limiting conditions with regard to local uptake will be described. The quantitative description of plasma and tissue binding is discussed, along with the notion of effective protein concentrations for the latter. Using these basic ideas, the fundamental mass balances describing the flow, diffusion, and reactions of the drug are presented. An example of the prediction of the pharmacokinetics of a strongly bound drug is used as an illustration of the methods, and this example also indicates the types of useful simplifications that can be made. The special, but important, case of linear binding is next derived, and an example involving the drug methotrexate will illustrate the principles involved. Finally, cytosine arabinoside will be used to indicate methods that can be used for rapidly metabolized drugs. Since existing examples are primarily utilized, this paper brings together a comprehensive collection of the several sets of physiologic data and modeling techniques that have been used for the past several years. It is hoped that this documentation will provide a useful basis for the those wishing to use this approach to pharmacokinetics.
5-Azacytidine is more active when administered parenterally than orally in the treatment of L1210 leukemic mice. Oral coadministration of tetrahydrouridine, a pyrimidine nucleoside deaminase inhibitor with no intrinsic antitumor activity, greatly increases the oral activity of 5-azacytidine. 5-azacytidine (or cytotoxic equivalent) blood levels in BDF mice are much higher after oral administration of the 5-azacytidine-tetrahydrouridine combination than when 5-azacytidine is administered alone by the same route. The therapeutic results (L1210 leukemia) achieved with the oral combination are similar to those observed with parenteral 5-azacytidine alone.
Twenty-two children with rhabdomyosarcoma were treated with combination chemotherapy using vincristine, actinomycin D, and cyclophosphamide for varying time periods. Chemotherapy, usually combined with radiation therapy, was given to early stage patients after they had had a com plete or partial tumor resection. Three of nine patients who had widespread metastatic (stage III) disease at initiation of therapy had complete tumor regression and four of nine had partial tumor regression. However, the median durations of response and survival were brief (3 and 8 months respectively). Five patients with localized resectable (stage I) disease have survived without evidence of tumor recurrence from 33 to 69 months after their initial diagnosis. Of eight patients with incompletely resected regional (stage IIB) disease, one has survived without disease recurrence for 36 months, thought the median survival time of the remaining seven patients was 14 months. In stage IIB patients the duration of response was proportional to the duration of chemotherapy which suggests that chemotherapy should be given for at least 18-24 months.
This paper describes a random study being conducted to compare the value of 5-fluorouracil plus diethylstilbestrol vs diethylstilbestrol alone and the value of 5-fluorouracil vs CCNU in the treatment of stage D adenocarcinoma of the prostate. We have established that similar normal values of acid phosphatase are encountered in serum and bone marrow of patients with nonmalignant and malignant diseases without osseous metastasis.
The rationale for extended-field radiation therapy in carcinoma of the prostate is discussed. The historical role of radiotherapy in prostatic cancer and some of the developments which have stimulated this broader approach to its therapy are reviewed.
Tissue concentration of 3H-actinomycin D have been determined in the rat, monkey, and dog after an iv dose of 0.6 mg/m2 body surface area. The drug-tissue half-life was determined for various tissues of the rat, monkey, and dog. A mean drug-tissue half-life of 47 hours was calculated for the tissues of the dog. Exceptions were the testis and brain. Significant concentrations of 3H-actinomycin D failed to accumulate in the brain. Although testis drug concentrations were lower than most other tissues evaluated, the drug-tissue half-life was significantly greater than that of other tissues. In all species studied 3H-actinomycin D was rapidly depleted from serum after iv dosage, with concomitant accumulation of drug in the tissues. 3H-actinomycin D was excreted via the biliary and urinary routes in all species studied. No metabolites of 3H-actinomycin D were detected in the bile or urine of the rat, monkey, or dog with the methods employed. When expressed on a body weight basis, body surface area doses were more than threefold greater in the rat than in the dog. However, the average ratio of concentration X time values (rat C X T/dog C X T) for 11 different tissues of the rat and dog was only 1.3. The results strongly suggest that an equivalent dose of actinomycin D, with dosage based on a body surface area basis, results in nearly equal tissue-drug exposure for most tissues in various mammalian species.
Mice bearing a 3-methylcholanthrene-induced fibrosarcoma (MCAM-7) transplant in the right leg underwent surgical excision of the tumor and showed specific resistance to subsequent challenges with that identical tumor line. An in vivo response to tumor-specific antigens (MCAM-7 antigen) solubilized by hypertonic potassium chloride was measured by 24-hour footpad swelling response in mice immunized to the tumor from which the antigens were extracted. These observations suggested that the transplantable MCAM-7 fibrosarcoma could produce immunity toward the solubilized MCAM-7 tumor antigens and that this tumor immunity could be measured by footpad swelling response to injection of the solubilized antigens, an indication of cell-mediated immunity. The footpad swelling response was also minotored in relation to the extent of tumor growth. Mice received MCAM-7 tumor transplants by injection of 5 times 10-6 tumor cells and were tested for footpad swelling response at intervals following tumor transfer. A significant footpad response to injected MCAM-7 antigens was present 10 days following tumor transfer; at this time signs of tumor growth were only minimally detectable. The footpad swelling response to injected antigens disappeared by 28 days following initial tumor transfer; at this time the tumor diameters were in excess of 1.0 cm. Surgical removal of tumor at this point promptly restored footpad responses within 24 hours. Similar techniques have been applied to patients bearing adenocarcinoma of the prostate, where skin testing was substituted for the measurement of footpad swelling in animals. Seven patients with known prostatic carcinoma were given intradermal injections of soluble tumor antigens extracted from their own tumors. Three of the seven patients exhibited a cutaneous delayed type hypersensitivity response to the injected autologous tumor extracts. No positivereactions were observed in response to solubilized components of control tissues, including benign prostatic hyperplasia. The significance of the demonstrated concomitant immunity in these patients has not been resolved. However, these observations suggest that some patients bearing adenocarcinoma of the prostate can exhibit an immunologic response to specific antigens present in their own neoplasms.
