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Biomedical subjects

M Colvin

Publications and source records attributed to M Colvin.

At least 55 records · Page 3Linked to original sources
PubMed1983

In vitro alteration of canine renal allografts with cyclophosphamide metabolites.

4-Hydroxycyclophosphamide (4-HCY) is generated spontaneously in cryoprecipitated plasma from synthesized 4-hydroperoxycyclophosphamide (4-HPCY); its immunosuppressive and cytotoxic effects seem to depend on milieu, temperature, time, and dosage. Our preliminary results suggest that prolonged canine renal allograft survival can be achieved with grafts exposed to CY metabolites (4-HPCY and PM) in vitro for 24 hr. Further studies with larger dosages (greater than or equal to 100 micrograms/ml of 4-HPCY) are indicated to test these suggestions conclusively.

Animals↗
PubMed1982

In vitro effects of 4-hydroperoxycyclophosphamide on human immunoregulatory T subset function. I. Selective effects on lymphocyte function in T-B cell collaboration.

The alkylating agent cyclophosphamide may suppress or enhance immune responses in vivo but is inactive in vitro unless metabolized by microsomal enzyme activation. 4-hydroperoxycyclophosphamide (4-HC) is a synthetic compound that is spontaneously converted in aqueous solution to the active metabolites. In this report, we examined the in vitro sensitivity of functional human T cell subsets to 4-HC in a polyclonal B cell differentiation assay and in the generation of mitogen-induced suppressor cells for effector B cell function. Con A-induced T suppression of B cell differentiation is completely abrogated by a 1-h pretreatment of T cells at very low concentrations of between 10(-2) and 20 nmol/ml, whereas inducer T cell function is sensitive only to concentrations in greater than 40 nmol/ml. The effects of 4-HC on suppressor T cells appear to occur at concentrations that do not result in DNA cross-linking or decreased blastogenesis. Con A-induced T suppressors are generated from within the OKT4+, OKT8- subset and are sensitive to low-dose 4-HC only before activation, whereas differentiated suppressor cells are resistant to concentrations in greater than 80 nmol/ml. Low-dose 4-HC pretreatment of the B cell population results in abrogation of immunoglobulin secretion when treated B cells are cocultured with unfractionated T cells, however, this effect is completely reversible if pretreated B cells are cocultured with T cells devoid of suppressor activity. These results demonstrate that human presuppressor cells for B-effector function differentiate in response to Con A from the OKT4+, OKT8- subset and are exquisitely sensitive to low concentrations of CYP whereas mature suppressor and inducer functions are resistant to all but very high concentrations in vitro. The differential sensitivity of functional T and B cell subsets to 4-HC in vitro can be a very useful probe in dissecting immunoregulatory interactions with man.

B-Lymphocytes↗
PubMed1982

Cyclophosphamide plasma and cerebrospinal fluid kinetics with and without dimethyl sulfoxide.

Ten patients with brain tumors and indwelling ventricular reservoirs were pretreated with 5% to 10% dimethyl sulfoxide (DMSO) (intravenous, oral, or both) and were then treated with 1.0 to 1.25 gm/m2 cyclophosphamide (CYC). All patients were also on anticonvulsants and dexamethasone. CYC and alkylating activity (alk act) in plasma and concomitant ventricular cerebrospinal fluid (CSF) were measured by gas chromatography and p-nitrobenzyl pyridine assay. CYC entered the CSF without difficulty and was lost from CSF more slowly than from plasma. Alk act did not enter CSF as well as did CYC. DMSO did not alter any measured aspect of CYC or alk act disposition. Specifically, it did not alter the CYC plasma half-life (t1/2), CSF t1/2, peak CSF: peak plasma CYC concentration ratio, or the urinary excretion of CYC. DMSO did not alter the plasma t1/2 or urinary excretion of alk act or the peak CSF:peak plasma concentration ratio of alk act. Our data show reduced plasma t1/2 of CYC and increased plasma and urinary alk act. This may reflect tht effect of long-term therapy with anticonvulsants or steroids.

Adult↗
PubMed1982

The course of nausea and vomiting after high-dose cyclophosphamide.

We studied the course of nausea and vomiting after high-dose cyclophosphamide (50-75 mg/kg) in 25 patients. Nausea was assessed with a visual analog scale and vomiting by patient report. The reliability and validity of these methods of assessment were established in separate studies of oncology patients. Nausea and vomiting developed between 6 and 12 hours after the start of a 1-hour cyclophosphamide infusion in about two thirds of the patients. Peak symptoms were at 12 hours. Vomiting had subsided in most of the patients by 24 hours, but nausea persisted. Although there was significant individual variation in the course of nausea and vomiting, we could identify no demographic, disease, drug, or treatment factors which were associated with more significant nausea and vomiting. Some of the variability in the onset, severity, and duration of nausea and vomiting may be related to individual differences in the metabolism of and susceptibility to cyclophosphamide. The visual analog scale may provide information about nausea not obtained by the more frequently employed categoric verbal rating scales. Suggestions for the treatment of nausea and vomiting after high-dose cyclophosphamide are made on the basis of the findings.

Adult↗
PubMed1982

Vomiting induced by cyclophosphamide and phosphoramide mustard in cats.

Cyclophosphamide and phosphoramide mustard produce significant vomiting. Cyclophosphamide is metabolized to phosphoramide mustard, which may ultimately contribute to vomiting after cyclophosphamide administration. The role of the chemoreceptor trigger zone (CTZ) in vomiting caused by these agents is unknown. We studied the emetic syndromes produced by iv and intracerebroventricular cyclophosphamide and phosphoramide mustard in unanesthetized normal and CTZ-ablated cats. Iv cyclophosphamide produced vomiting unpredictably, with a mean latency of 54 +/- 9 mins (mean +/- SE) in cats that vomited. A dose-response relationship was found for phosphoramide mustard-induced emesis. A dose of 200 mg/kg was consistently effective, with a mean latency of 127 +/- 6 mins. Neither agent produced predictable emesis by the intracerebroventricular route of administration. One of four CTZ-ablated cats vomited after 300 mg/kg of cyclophosphamide. Since cyclophosphamide was an unpredictable emetic stimulus, it was not possible to further evaluate the effect of CTZ ablation on cyclophosphamide-induced vomiting. However, CTZ-ablated cats given 200 mg/kg of phosphoramide mustard vomited significantly less frequently (P = 0.05 by chi-square test) and with a longer latency than nonablated animals. A temporary, severe neurotoxic reaction was observed in cats receiving greater than or equal to 3400 mg/kg of cyclophosphamide, which may have had an inhibitory effect on emesis. Phosphoramide mustard was found to be a potent emetic stimulus in cats and may contribute to the emetic response following cyclophosphamide administration. Analysis of latency data suggests that in the cat other cyclophosphamide metabolites may also contribute to the emetic syndrome.

Animals↗
PubMed1981

Neonatal imprinting and hepatic cytochrome P-450. II. Partial purification of a sex-dependent and neonatally imprinted form(s) of cytochrome P-450.

A new form of cytochrome P-450 was partially purified from hepatic microsomes of neonatally imprinted rats (adult male and adult male castrated at four weeks of age). This new form of cytochrome P-450 appears to have an apparent molecular weight of approximately 50,000 daltons as judged by sodium dodecyl sulfate polyacrylamide gel electrophoresis. It appears that this form of cytochrome P-450 is either absent or present in low concentrations in cytochrome P-450 preparations isolated from neonatally nonimprinted rats (adult female and adult male castrated at birth). Reconstitution of testosterone hydroxylase and benzphetamine N-demethylase activities of this partially purified cytochrome P-450 revealed that the presence of testosterone 16 alpha-hydroxylase activity, an imprintable microsomal enzyme, was in parallel with the imprinting status of the animals; a significantly higher activity was detected in the neonatally imprinted than that of the nonimprinted animals. This was in contrast to the nonimprintable benzphetamine N-demethylase, testosterone 7 alpha- and 6 beta-hydroxylase activities which exhibited no correlation with the imprinting status of the animals. We have prepared antisera from rabbits using the partially purified cytochrome P-450 preparations from adult male rats as antigens. These antisera inhibited microsomal testosterone 16 alpha- and 7 alpha-hydroxylase activities in a concentration-dependent manner, without impairing 6 beta-hydroxylase activity. These data suggest that the partially purified cytochrome P-450 from adult male rats consists of both imprintable (16 alpha-) and nonimprintable (7 alpha-) testosterone hydroxylase activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Cyclophosphamide and dimethylsulfoxide in the treatment of squamous carcinoma of the lung. Therapeutic efficacy, toxicity, and pharmacokinetics.

To determine whether dimethylsulfoxide (DMSO) can potentiate antitumor activity of cyclophosphamide (CYC) in patients with squamous cell carcinoma of the lung, 14 patients were treated with 5 l of a 5% or 6% DMSO solution PO over 3 days and 1,500 mg CYC/m2 IV as a 60-min infusion on the third day of treatment. Serial blood, CSF, and urine samples were collected to assess the pharmacokinetics of CYC. Courses were repeated every 3-4 weeks. No antitumor responses were observed. Toxicity was mainly hematologic and similar to that of CYC alone. There was one death from infection during granulocytopenia. Nonhematologic toxicity was moderate to severe and included nausea (14 patients) and vomiting (five patients). The plasma pharmacokinetics of CYC in this study are similar to previously reported results for CYC alone, but the 24-h urinary excretion of CYC in our study is much lower than previously reported. Further studies in tumors more responsive to CYC may be warranted.

Adult↗
PubMed1980

Analysis of the anticancer drugs VP 16-213 and VM 26 and their metabolites by high-performance liquid chromatography.

A rapid and convenient high-performance liquid chromatographic procedure for the analysis of the clinically useful anticancer agents VP 16-213 and VM 26 is described. The drugs, which are semi-synthetic derivatives of the natural product podophyllotoxin, are extracted from plasma with chloroform. The extracts are evaporated to dryness, reconstituted in methanol, and chromatographed on a reversed-phase microparticle C18 column using isocratic elution with a mixture of methanol--water (60:40). Each drug is used as the internal standard for the other. Quantitation to 500 ng/ml (0.85 nmole/ml) plasma is based on peak height ratios using UV detection at 254 nm. Patient plasma concentration versus time data agree well with previously published data obtained using radiolabelled drug. Investigations into the nature of the hydroxy acid metabolite of VP 16-213, carried out using paired-ion chromatography with tetrabutylammonium bromide and fluorescence detection, are described. Also, a unique separation of VP 16-213 and a possible metabolite, the isomer, picro VP 16-213, is described.

Adult↗
PubMed1980

Elimination of acute myelogenous leukemic cells from marrow and tumor suspensions in the rat with 4-hydroperoxycyclophosphamide.

Cell suspensions of normal rat marrow mixed with rat acute myelogenous leukemic cells were prepared and incubated in vitro with graded doses of 4-hydroperoxycyclophosphamide (4HC). The cell suspensions were injected into rats prepared with a lethal dose of total body irradiation. Animals injected with these cells survived fatal irradiation induced aplasia. In a dose related manner 4HC was able to "purge" tumor cells from the cell mixtures. Thus, animals given cell suspensions incubated with the lower doses of 4HC showed prolonged survival before death from leukemia and animals given cell suspensions incubated with higher doses of 4HC survival lethal irradiation without the subsequent appearance of leukemia. These studies clearly establish that tumor cells may be eliminated from normal marrow suspensions without completely destroying the pluripotent stem cells.

Animals↗
PubMed1980

Stability of carmustine in the presence of sodium bicarbonate.

The stability of carmustine in 5% dextrose injection and 0.9% sodium chloride injection, with and without added sodium bicarbonate, was studied at room temperature. Solutions of carmustine (0.1 mg/ml) in dextrose or saline with and without added sodium bicarbonate (1 meq/ml) were prepared. After 0, 15, 30, 60, and 90 minutes, aliquots of each test solution were analyzed for carmustine using the Bratton-Marshall test with absorbance at 540 nm. There was no significant decomposition of carmustine in dextrose or saline alone. However, the addition of sodium bicarbonate increased carmustine degradation; after 90 minutes, approximately 73% of the active drug remained. It is recommended that carmustine be neither admixed with nor administered piggyback with parenteral infusion solutions containing sodium bicarbonate.

Bicarbonates↗
PubMed1980

Quantitation by gas chromatography-chemical ionization-mass spectrometry of phenylalanine mustard in plasma of patients.

An unambiguous and sensitive method based on gas chromatography-chemical ionization-mass spectrometry has been developed to quantitate L-phenylalanine mustard and has been applied to measure levels in plasma of five patients receiving 0.15 to 0.25 mg/kg (10 to 17 mg) of the drug p.o. Peak plasma levels of 50 to 190 ng/ml were found to occur between 0.7 and 2.3 hr after ingestion. The time for the plasma level to fall to one-half of the peak value varied from 0.6 to 3 hr, and very low levels (less than 2 ng/ml) were present by 24 hr.

Adenocarcinoma↗
PubMed1979

Comparative effects of cyclophosphamide, isophosphamide, 4-methylcyclophosphamide, and phosphoramide mustard on murine hematopoietic and immunocompetent cells.

The effects of equimolal doses of cyclophosphamide (CY), isophosphamide (IP), 4-methylcyclophosphamide (4-MCY), and phosphoramide mustard (PM) on murine hematopoietic spleen colonies and adoptively transferred antibody-forming cells in vivo were compared. Equimolal doses of the drugs produced significantly different effects. All the drugs exerted an increasing effect against the ability of adoptively transferred immunocompetent cells to produce a significant anti-sheep red blood cell titer as the length of time between cell transfer and drug administration was increased. The maximum effect was seen when a drug was given 48--72 hours after antigen and spleen cell transfer. CY and IP produced significantly greater immunosuppressive effects than did the other drugs at all times after cell transfer and at all doses administered. PM had the least immunosuppressive effect at each dose evaluated. Against hematopoietic spleen colonies, the cytotoxic effects of 4-MCY and PM were similar and, at most doses studied, significantly greater than the effect of either CY or IP. Inasmuch as PM is an active metabolite of CY, it appeared either that one of the prior metabolites of CY was responsible for this marked immunosuppressive effect or that due to differences in polarity, PM was differentially distributed within the two cell systems as compared to CY. The differences in hematopoietic effects among all drugs were much less than those seen against immunocompetent cells and were not dependent on time of drug administration.

Animals↗
PubMed1979

Comparison of mutagenicity, antitumor activity, and chemical properties of selected nitrosoureas and nitrosoamides.

A number of nitrosoureas and nitrosoamides have been compared with respect to mutagenicity for Salmonella typhimurium, in vitro cytotoxicity, in vivo toxicity and antitumor activity against murine L1210 leukemia, and chemical properties. Despite chemical similarities between the nitrosoureas and nitrosoamides, they show important differences in biological activity. Some of the nitrosoureas are very active antitumor agents, and they are less mutagenic than are the corresponding nitrosoamides, which lack antitumor activity.

Animals↗