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Biomedical subjects

G L Wampler

Publications and source records attributed to G L Wampler.

At least 19 recordsLinked to original sources
PubMed1992

Relationships between various uses of antineoplastic drug-interaction terms.

In in vitro testing, no pharmacologic synergism has been found for the combination of cisplatin and etoposide in P388 leukemia in contrast to the demonstration of therapeutic synergism in the same model. No pharmacologic synergism has been found for the same combination in the treatment of four small-cell lung-cancer cell lines, although clinical results obtained using this combination in small-cell lung cancer and other cancers suggest a therapeutic advantage. The popular concept of synergy, implying a therapeutic advantage, is different from the pharmacologic meaning, which generally implies that less drug is required in a combination for an equal effect. Therapeutic advantage may be obtained regardless of whether drugs are synergistic in the pharmacologic sense in the treatment of a tumor. To gain a more comprehensive insight into concepts of drug interaction, it is important to recognize that the type of drug interaction seen is dependent on the drug doses used and may vary with the treatment of different cell lines. All of these factors complicate the use of the word synergism, or any associated term, in a categorical manner to describe the effects of combinations of antineoplastic drugs.

Animals↗
PubMed1992

Calculation of received dose intensity for combinations of drugs using small-cell lung carcinoma treatment regimens as examples.

Programs are presented for the calculation of received dose intensity in combination chemotherapy regimens. These provide methods for determining the final dose intensity, the mean cumulative dose intensity together with its standard error, and other tabular and graphic summaries. Two ways of dividing patients into high and low received-dose-intensity groups are proposed. Methods are illustrated using data from Mid-Atlantic Oncology Program (MAOP) 2183, a phase III evaluation of a six-drug alternating combination vs a three-drug "standard" combination treatment for extensive small-cell lung cancer. Comparisons of received dose intensity with demographic and outcome variables are presented.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

A study of oral etoposide, infusional cisplatin, and infusional 5-fluorouracil for locally advanced or metastatic non-small-cell lung cancer. A Mid-Atlantic Oncology Program study.

A combination of oral etoposide, infusional cisplatin (24-hr) and infusional 5-fluorouracil (5-day) was used to treat 87 patients with non-small-cell lung cancer in a Phase II trial. Twenty-six patients were Stage IIIB, and 61 patients were Stage IV (new international classification). The regimen was well tolerated, with 49% grade 3 or 4 toxicities of all types. Response rates, partial and complete, were 40%, (95% confidence interval: 30%, 51%) for Stage IV patients and 20% (95% confidence interval: 10%, 32%), in Stage IIIB. An additional 68% of patients in Stage IIIB and 45% of patients in Stage IV achieved stable disease and had a median survival of 8.8 months, similar to that of patients in partial remission. Median survival was 5.6 months (95% confidence interval: 4.4 months, 10.8 months) for Stage IV patients and 11.0 months (95% confidence interval: 8.8 months, 12.4 months), for Stage IIIB. Of interest was the finding of a higher response rate in patients with a shorter duration of symptoms (less than 6 months versus greater than 6 months).

Administration, Oral↗
PubMed1992

A pilot study of intensive weekly chemotherapy for extensive disease small-cell lung carcinoma.

An intensive weekly chemotherapeutic treatment for extensive disease small-cell lung cancer was piloted in 14 patients. The regimen consisted of 6 drugs. Two drugs were given each week for a total of 12 weeks of treatment. Modifications were required in the protocol to attempt to overcome excessive toxicity. Unexpected toxicity included anemia requiring transfusions in 8 of 10 patients completing treatment, sepsis in 8 of 14 with 3 related deaths, and prolonged grade III motor neurotoxicity in 2 patients. All 3 patients who died of sepsis had shown evidence of response, and 8 of the remaining 11 had 90% or greater tumor shrinkage. Two others had a partial response. Median survival time for all patients was 9.3 months.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

A prospective randomized comparison of protracted infusional 5-fluorouracil with or without weekly bolus cisplatin in metastatic colorectal carcinoma. A Mid-Atlantic Oncology Program study.

One hundred eighty-four patients with advanced measurable colorectal cancer not previously treated with chemotherapy were entered into a prospective randomized clinical trial by the Mid-Atlantic Oncology Program (MAOP) to assess the value of weekly cisplatin (20 mg/m2) when added to a protracted schedule of 5-fluorouracil (5-FU) infusion (PIF) at 300 mg/m2/d for 10 weeks of every 12 weeks. The liver was the primary indicator lesion in approximately 75% of the study group. All tumor measurements required radiographic confirmation. The response rate in the PIF alone arm was 35% (29 of 83; 95% confidence interval [CI], 25% to 46%) compared with 33% (28 of 85; 95% CI, 23% to 44%) for the arm in which weekly cisplatin was added to PIF. The median survival times were 11.8 and 11.2 months in the two groups. Weekly cisplatin does not appear to add to the effectiveness of PIF in colorectal carcinoma.

Aged↗
PubMed1991

Case report of metastatic familial pheochromocytoma treated with cisplatin and 5-fluorouracil.

We report on a rare case of malignant pheochromocytoma in a patient with a family history of this disease. After three cycles of treatment with cisplatin and 5-fluorouracil, a decrease in the need for antihypertensive treatment occurred, which lasted almost 2 years despite the discontinuation of chemotherapy. The patient showed an objective response, which was technically a minor response, although in this slow-growing tumor it was of major clinical significance. This chemotherapy regimen may play a role in the management of malignant pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed1991

Synthesis of potential dual-acting radiation sensitizer antineoplastic agents: 2,2-dimethylphosphoraziridines containing 2-nitroimidazoles or other electron-affinic moieties.

In view of the in vivo demonstrated radiation-potentiating activities of several previously studied 2,2-dimethylphosphoraziridines, six new compounds incorporating the bis(2,2-dimethyl-1-aziridinyl)phosphinyl moiety, together with an electron-affinic group such as 2-nitroimidazole or nitrobenzyl, have been synthesized and tested (1) in vitro for ability to increase the effect of X-irradiation under hypoxic conditions on V-79 Chinese hamster lung fibroblast cells, (2) in vivo for antitumor activity in the absence of radiation against P388 leukemia in mice, and (3) in a preliminary experiment with compound 10 only, in combination with whole-body gamma-radiation, using the P388 leukemia mouse model for in vivo radiation-potentiating activity. The chemical-alkylating activities and hydrolytic behavior of these compounds, as well as their antitumor activities without radiation, were found to be comparable to those of other 2,2-dimethylphosphoraziridines, while their in vitro radiosensitizing activities were at low concentrations generally comparable to that of misonidazole, with compound 8 showing superior activity. At higher concentrations, only compound 10 was sufficiently soluble and nontoxic to the cells for evaluation in this assay. Thus, the bis(2,2-dimethyl-1-aziridinyl) phosphinyl moiety does not seem to have contributed to the hypoxic radiosensitizing activities (only to the cytotoxicities) of the electron-affinic moieties in this in vitro assay. In comparison, the prototype 2,2-dimethylphosphoraziridine, ethyl [bis(2,2-dimethyl-1-aziridinyl) phosphinyl]carbamate (AB-132), showed at nontoxic doses no radiosensitizing activity in this assay, and at cytotoxic doses increased the cell-killing effect of each given dose of X-radiation additively under both hypoxic and oxic conditions. Conversely, only the 2,2-dimethylphosphoraziridine moiety appeared to participate in the moderate "therapeutic radiation-potentiating" activity indicated by compound 10 in the in vivo experiment using the P388 leukemia model (on day 1), as the misonidazole standard was inactive in this nonhypoxic system. Clearly, the mechanism of the in vivo observed radiation-potentiating effect of AB-132 and other 2,2-dimethylphosphoraziridines is different from that of the hypoxic radiosensitizers, but the possible synergism between the two biologically active moieties of the new compounds could not be demonstrated with the experimental models so far employed.

Animals↗
PubMed1991

A method for determining schedule dependency in tissue culture.

A dual-exposure drug treatment of cell lines in tissue culture provides a possible method for determining schedule dependency. This is suggested by results of treatment of human small cell lung carcinoma NIH H209 and murine L1210 leukemia cell lines with cisplatin, a non-schedule-dependent drug, and etoposide, a schedule-dependent drug. Nonlinear least squares was used to estimate the dose-response surface. The estimated regression coefficients for the effect of the first dose compared to that of the second dose support the premise that cisplatin is not schedule dependent. Unlike cisplatin, the second dose of etoposide was shown to be more effective than the first dose in the human small cell carcinoma line. This agrees with known clinical results where multiple etoposide dosing has been shown to be more effective and confirms schedule dependency. This methodology, or a refinement, may offer another tool for studying schedule dependency of drugs using tissue culture methods.

Animals↗
PubMed1991

Dichloromethotrexate, infusional cisplatin, and infusional 5-fluorouracil for locally advanced or metastatic non-small cell lung cancer. A MAOP study.

The combination of dichloromethotrexate, cisplatin, and infusional 5-fluorouracil was evaluated as treatment for non-small-cell lung cancer in a phase II trial using 43 evaluable patients. Grade III or IV toxicity included thrombocytopenia (21%), leukopenia (14%), nausea/vomiting (14%), mucositis (9%), infection (5%), and other (16%). There were six responders (14%), with a 95% confidence interval of [5%, 28%]. Two additional patients achieved a 50% reduction in cross-sectional tumor size that was not documented twice. Median survival time was 6.5 months. This combination is not considered sufficiently active for further evaluation in this disease.

Adult↗
PubMed1991

A study of infusional cisplatin and infusional fluorouracil for locally advanced or metastatic non-small-cell lung cancer: a Mid-Atlantic Oncology Program study.

A combination of cisplatin administered as a 24-hour infusion and fluorouracil administered as a 5-day infusion was used to treat 97 patients with non-small-cell lung (NSCLC) cancer in a phase II trial. Thirty patients had stage IIIB disease; 67 patients, stage IV disease (new international classification). Patients with stage IIIB disease also received thoracic radiation after chemotherapy. The regimen was well tolerated, with 24% or less grade 3 or greater toxicities of all types. One toxic death was attributed to fluid overload. The response rate, partial and complete, was 43% (95% confidence interval, 27% to 63%), and median survival was 13.8 months for patients with stage IIIB disease. Response rates refer to the chemotherapy response. For patients with stage IV disease, the response rate was 34% (95% confidence interval, 24% to 47%), and median survival was 6.2 months. On this regimen, stable-disease patients with stage IV disease had survivals at least equal to responders.

Adult↗
PubMed1991

Comparison of cyclophosphamide, doxorubicin, and vincristine with an alternating regimen of methotrexate, etoposide, and cisplatin/cyclophosphamide, doxorubicin, and vincristine in the treatment of extensive-disease small-cell lung carcinoma: a Mid-Atlantic Oncology Program study.

An alternating regimen for the treatment of extensive-disease small-cell lung cancer (SCLC) was compared with standard treatment with cyclophosphamide, doxorubicin, and vincristine (CAV) in 170 patients. Overall severity of toxicity was similar in both arms, with four toxic deaths in each arm (4.7%). Response results were also similar, with 54% complete and partial responses with the standard regimen and 53% complete and partial responses with the alternating regimen. Median survival time was 6.9 months with the standard regimen and 9.2 months with the alternating regimen (P = .078). The 2-year survival rate was 1.2% for the standard regimen and 4.7% for the alternating regimen. Survival benefit for treatment with the alternating regimen reached statistical significance only in those subsets of patients with poorer prognosis (male sex, performance status 3, liver metastases, bone marrow metastases, and oat cell histologic subtype).

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Combination of 5-fluorouracil and cyclophosphamide in L1210 and P388 leukemias with changes in optimum treatments as a function of the age of the L1210 tumor at first treatment.

The interaction of 5-fluorouracil and cyclophosphamide in the treatment of L1210 and P388 leukemias was studied using response surface methodology. Single dose treatment of each drug was administered simultaneously or with a 24-hr interval between 5-fluorouracil and cyclophosphamide to the advanced tumors or at various times after L1210 inoculation. While at low doses the action of the combination of the two drugs was greater than expected, there was no therapeutic synergism if the drugs were given together (optimum doses cyclophosphamide 366 mg/kg and 364 mg/kg, respectively, in advanced L1210 and P388 leukemias) or in the early tumor when cyclophosphamide was given 24 hours after 5-fluorouracil. In the advanced tumor, using the regimen employing a 24-hr interval between drugs, therapeutic synergism could be demonstrated (optimum doses 5-fluorouracil 130 mg/kg followed by cyclophosphamide 248 mg/kg in advanced L1210 leukemia and 5-fluorouracil 110 mg/kg followed by cyclophosphamide 263 mg/kg in advanced P388 leukemia). The evidence generated suggested that improved therapy could be found in two separate regions of the treatment space, raising the possibility of more than one mechanism of drug interaction. The location of the optimal treatment depended on the tumor burden at the time treatment was initiated. A shift from one region to the other occurred after 4-6 days of tumor growth when the original inoculum was 10(5) i.p. L1210 cells. Another more obvious conclusion that can be drawn is that treatment was less effective as the tumor became more advanced. The notion that different tumor stages may require different ratios of drugs in a clinically useful combination should receive attention.

Animals↗
PubMed1987

Demonstration of a schedule-dependent therapeutic synergism utilizing the interacting drugs methotrexate and teniposide in L1210 leukemia.

When three variables require simultaneous adjustment for treatment optimization, the experimental determination of the optimum treatment becomes more complicated than generally appreciated, especially when one variable is the interval between drug administrations. Molecular pharmacological studies at this institution suggest that teniposide, in doses that are achievable in vivo, blocks methotrexate efflux from cells, enhancing formation of methotrexate polyglutamates which are active retentive forms of the drug. Hence, the combination might show a synergistic effect if teniposide is given at an appropriate time in relation to administration of methotrexate. This paper considers the problem of estimating the optimal dose levels and timing of administration of these drugs in B6D2F1 mice bearing L1210 leukemia in vivo as a model for the analysis of multidrug regimens when time and dose are variables. Because of the complexity of these experiments, an adaptive approach was applied. Three cycles of treatment were given using methotrexate at 0-400 mg/kg, teniposide at 0-60 mg/kg, and an interval of 0-54 hours between the two drugs. The single drugs prolonged median survival up to 24 days under the conditions of these experiments. The combination given simultaneously resulted in median survival of up to 33.5 days, while use of an appropriate interval between drugs prolonged median survival to greater than 50 days. An analysis of the underlying dose-time response gives a much better appreciation of the relationships among the variables. The concept that optimal doses included less methotrexate and more teniposide as the interval between drugs is increased was developed only through modeling. This finding is critical in demonstrating the importance of including all nonnegligible variables in the experimental design if the results are to be considered valid. Confidence regions about the optimum dose and about the response at the optimum provide a sound basis for a claim of therapeutic synergism as demonstrated by use of a scheduling variable in the experiment design. A nonproportional hazards analysis permits the conclusion of nonproportionality and emphasizes the contribution of methotrexate to optimal short-term survival (15-24 days) and teniposide to long-term survival (24-39 days).

Animals↗
PubMed1979

A new steroidal alkylating agent with improved activity in advanced murine leukemias.

The homo-aza-steroidal ester of [p-[bis(2-chloroethyl)amino]phenoxy] acetic acid, 3 beta-hydroxy 13 alpha - amino - 13,17 - seco - 5 alpha-androstan-17-oic-13,17-lactam-p-bis(2-chloroethyl)aminophenoxyacetate, gave a 100% increase in lifespan over controls in the treatment of L1210 leukemia by IP administration on a days 1 and 4 treatment schedule. This ester gave a maximum activity of 383% increased lifespan over controls in the treatment of P388 leukemia by IP administration on a daily treatment schedule. Activity in advanced L1210 (41% increased lifespan) and P388 leukemias (173% increased lifespan) was maintained, indicating that this compound is the most promising of a number of congeners tested to date.

Alkylating Agents↗
PubMed1979

Clinical study of hydrazine sulfate in advanced cancer patients.

Twenty-five patients with a variety of solid tumors were treated with hydrazine sulfate. Hydrazine was given orally in the form of 60 mg capsules from one to four times daily. No patient had a 50% reduction of tumor size. Subjective benefit was seen in three patients but it was of brief duration.

Adolescent↗
PubMed1979

Synthesis of hydroxy- and amino-substituted benzohydroxamic acids: inhibition of ribonucleotide reductase and antitumor activity.

Benzohydroxamic acids inhibit mammalian ribonucleotide reductase and exhibit antineoplastic activity in L1210 leukemic mice. Five new hydroxy- and amino-substituted benzohydroxamic acids (3,4- and 3,5-OH, 3,4-NH2, 2,3,4- and, 3,4,5-OH) were prepared and tested along with 12 previously reported benzohydroxamic acids (BHA) for enzyme inhibition and antitumor activity. The most potent enzyme inhibitor in this series was 2,3,4-OH-BHA (ID50 = 3.5 microM), which is 140 times more potent than hydroxyurea, but its toxicity limited the antitumor activity to a 30% increase in life span of L1210 bearing mice at 125 (mg/kg)/day ip for 8 days. The most effective antitumor agent in this series was 3,4-OH-BHA which prolonged the life span of L1210 bearing mice 103% at 600 (mg/kg)/day ip for 8 days.

Animals↗