PubMed Health⌕ Search

Biomedical subjects

M H Marshall

Publications and source records attributed to M H Marshall.

At least 19 recordsLinked to original sources
PubMed1993

In vitro cytotoxicity of hepsulfam against human tumor cell lines and primary human tumor colony forming units.

Hepsulfam (sulfamic acid 1,7-heptanediyl ester, NSC 329680) is an alkylating agent currently in Phase I clinical trials. Hepsulfam was developed as an analog of busulfan, an alkylating agent that is used to treat patients with chronic myelogenous leukemia and for marrow ablation prior to bone marrow transplantation. The objective of this study was to identify the spectrum of human tumor cells that were sensitive to hepsulfam. The following three cytotoxicity assays were employed to evaluate the in vitro cytotoxic potential of hepsulfam: 1) primary human tumors were exposed to three levels of hepsulfam for a one hour or continuous exposure, and growth in soft agar was determined; 2) human non-tumor cells and tumor cell lines were compared in an assay that measured the conversion of 14C-glucose to 14CO2 as an index of viability; and 3) the toxicity of hepsulfam to hematopoietic progenitor cells was determined in a progenitor cell colony forming assay. Cytotoxicity was not observed for human tumor cells following one hour hepsulfam exposures; in contrast, marked dose-dependent cytotoxicity was observed with continuous exposures. In human tumor cell lines, the cytotoxicity of hepsulfam was compared directly with busulfan at equimolar concentrations. Hepsulfam was more cytotoxic than busulfan in all cell lines tested. Cytotoxic activity was seen in lung, melanoma, kidney, breast, colon, ovary and brain tumor cells. These results, along with the information obtained from Phase I trials, will facilitate selection of patients who could receive this agent in Phase II efficacy trials.

Antineoplastic Agents↗
PubMed1992

Activity of topotecan, a new topoisomerase I inhibitor, against human tumor colony-forming units in vitro.

BACKGROUND: Topotecan [(S)-9-dimethylaminomethyl(10-hydroxy-camptothecin), NSC 609699, SK&F 104864A], a semisynthetic analogue of the natural product camptothecin, is a cell cycle-specific drug that exerts antineoplastic activity through inhibition of topoisomerase I. Currently, topotecan is undergoing phase I and early phase II clinical trials. The dose-limiting toxicity for topotecan is myelosuppression. PURPOSE: Our purpose was to determine plasma concentrations and exposure times necessary for optimal clinical activity and tumor types that may be responsive in phase II clinical studies of topotecan. METHODS: A soft-agar cloning system assay was used to determine the in vitro effects of topotecan against cells from biopsy specimens of colorectal, breast, lung, ovarian, renal cell, and gastric cancers and cancers of unknown primary origin. We studied 141 freshly explanted tumor specimens, using 1-hour exposure to topotecan, and 80 were studied using continuous exposure. A decrease in tumor colony formation resulting from drug exposure was considered an in vitro response if survival of colonies was up to 50% of that in controls. RESULTS: With 1-hour exposure, in vitro responses were seen in 10% and 25% of assessable tumor specimens at final topotecan concentrations of 1.0 and 10.0 micrograms/mL, respectively. With continuous exposures at concentrations of 0.1 and 1.0 micrograms/mL, in vitro response rates were 34% and 76%, respectively. Specific activity was seen against colorectal, breast, non-small-cell lung, ovarian, and renal cell cancers, with responses observed in 27%, 25%, 32%, 39%, and 83%, respectively, of assessable tumor specimens after continuous exposure to 0.1 micrograms/mL topotecan. A subset of tumor specimens resistant to doxorubicin or fluorouracil was sensitive to topotecan, and the difference in sensitivity was statistically significant. In addition, some of the tumor specimens resistant to cyclophosphamide and etoposide were also sensitive to topotecan. CONCLUSIONS: Topotecan appears to be active in vitro against a variety of human tumors, including a subgroup resistant in vitro to standard antineoplastic agents. If plasma levels of 0.1 micrograms/mL can be achieved for prolonged periods of time in ongoing clinical trials, topotecan should have substantial clinical activity. IMPLICATIONS: Further clinical development of topotecan is warranted.

Antineoplastic Agents↗
PubMed1992

Lack of effects of recombinant human interleukin-4 on in vitro colony formation of freshly explanted human tumor cells.

Interleukin-4 is a highly pleiotropic T-cell derived lymphokine that has been reported to stimulate a host cell-mediated antitumor response. Recombinant human interleukin-4 (rhuIL-4) is currently undergoing clinical phase I trials. We have studied the growth modulating effects of rhuIL-4 on a variety of freshly explanted human tumor specimens using an in vitro soft agar cloning system. Final concentrations of 0.1 to 10 ng/ml were used in continuous incubation experiments. Of 147 specimens, 73 (50%) were evaluable for the determination of tumor growth modulating activity. The most common tumor types recruited included breast, non-small cell lung, ovarian cancer and melanoma. Stimulation of tumor colony forming units (colony formation > or = 1.5 x controls) was observed in 0/73 tumors. Similarly, only 1/73 (1.3%) specimens (a non-small cell lung cancer) had a significant decrease in tumor colony forming units (colony formation < or = 0.5 x controls) at 1 ng/ml. We conclude that rhuIL-4 is not a direct modulator of tumor colony formation in vitro. However, antitumor effects could perhaps be achieved in vivo via the immune-modulating effects of Interleukin-4.

Humans↗
PubMed1992

Activity of a recombinant transforming growth factor-alpha-Pseudomonas exotoxin hybrid protein against primary human tumor colony-forming units.

Transforming growth factor-alpha-Pseudomonas exotoxin-40 (TP40) is a recombinant fusion protein. TP40 consists of the entire human transforming growth factor-alpha (TGF alpha) protein fused to a 40,000 Da. segment of the Pseudomonas exotoxin A protein. TP40 is a bifunctional molecule that possesses the epidermal growth factor (EGF) receptor binding properties of TGF alpha and the cell killing properties of Pseudomonas exotoxin A. These properties make TP40 a selective cytotoxic agent that kills EGF receptor bearing cells. TP40 has been shown to effectively kill human tumor cell lines that possess EGF receptors in vitro and in nude mice. In the present study, TP40 was tested against tumors taken directly from patients and grown in a soft agar human tumor cloning system. A total of 107 patients' tumors (taken from patients with tumors refractory to chemotherapy) were tested with a continuous exposure to 0.5-50 nM concentrations of the agent. TP40 exhibited a clear dose response effect against a wide variety of human solid tumor colony-forming units with greater than or equal to 84% of evaluable tumors responding at a drug concentration greater than or equal to 24 nM. When used as a continuous exposure, concentrations of TP40 as low as 5 nM demonstrated substantial in vitro activity. This activity included cytotoxicity against breast, colorectal, endometrial, head and neck, non small-cell lung, gastric, sarcoma, and pancreatic cancer tumor colony-forming units. Additional in vivo testing of this compound is warranted.

Dose-Response Relationship, Drug↗
PubMed1992

Preclinical activity of ilmofosine against human tumor colony forming units in vitro.

Ilmofosine (BM 41.440, 1-hexadecylthio-2-methoxymethyl-rac-glycero-3-phosphocholine) is a synthetic alkyl lysophospholipid analog with activity against a variety of tumor models in vitro and in vivo. The i.v. form is presently undergoing early clinical investigation in phase I trials. In order to help define types of tumors that might be clinically sensitive to this agent we have studied the anti-tumor effects of ilmofosine against a variety of freshly explanted human tumor specimens using an in vitro soft agar cloning system. Final concentrations of 1.0-30 microgram/ml were used in continuous incubations experiments. Of 348 specimens tested, 134 (39%) were evaluable for determination of tumor growth modulating activity. The most common tumor types recruited included non-small cell lung, breast, colorectal, ovarian, renal cell cancer and melanoma. A concentration-dependent increase in the frequency of inhibited tumor specimens was observed with 6/134 (4%) sensitive specimens at 1 microgram/ml as compared with 113/133 (85%) sensitive specimens at 30 micrograms/ml (p less than 0.0000005). We conclude that ilmofosine is active against a variety of tumors in vitro. Clinical phase II trials with ilmofosine including the tumor types with in vitro sensitivity are warranted if adequate plasma concentrations of this agent can be reached in patients.

Drug Screening Assays, Antitumor↗
PubMed1992

Activity of 2',2'-difluorodeoxycytidine (Gemcitabine) against human tumor colony forming units.

2',2'-Difluorodeoxycytidine (LY 188011, Gemcitabine) is a novel pyrimidine antimetabolite with promising activity in preclinical models for leukemia and solid tumors. Phase I clinical trials with the agent are ongoing. In order to better define types of tumors with clinical sensitivity to Gemcitabine (to help target phase II trials), we have studied the antitumor effects of this agent against a variety of freshly explanted human tumor specimens using an in vitro capillary soft agar cloning system. Final concentrations of 2.0-200 micrograms/ml were used for short-term (1 h) and continuous incubations experiments. Using a short-term incubation, 94/215 (44%) tumor specimens were evaluable for the determination of antitumor activity. The most common tumor types studied included colorectal, breast, non-small cell lung, ovarian cancer, kidney and melanoma. A concentration-dependent increase in the frequency of inhibited tumor specimens was noted (2 micrograms/ml: 6/94 specimens, 20 micrograms/ml: 13/94 specimens, 200 micrograms/ml:33/94 specimens; p less than 0.0001). A similar increase in tumor growth inhibition was found using a continuous incubation (2 micrograms/ml: 0/14 specimens, 20 micrograms/ml: 1/14 specimens, 200 micrograms/ml: 7/14 specimens; p less than 0.001). We conclude that Gemcitabine is an active antitumor agent against tumor colony forming units from a variety of human malignancies if sufficiently high concentrations can be achieved. The agent should be evaluated for Phase II clinical activity against those tumor types.

Antimetabolites, Antineoplastic↗
PubMed1992

Effects of recombinant human interleukin-1 alpha on clonogenic growth of primary human tumors in vitro.

Interleukin-1 alpha (IL-1 alpha) is a low-molecular-weight cytokine that regulates proliferation and differentiation of lymphatic and myeloid cells. It also has pleiotropic activity on a variety of other target cells and acts as an important mediator of inflammation and septic shock. Recombinant human IL-1 alpha (rhIL-1 alpha) is undergoing clinical evaluation of its potential as an anticancer agent. We have studied the growth modulating effects of rhIL-1 alpha on a variety of freshly explanted human tumor specimens using an in vitro soft agar cloning system. Final concentrations of 0.01-100 ng/ml were used in continuous incubation experiments. Of 139 specimens tested, 56 (40%) were evaluable for determination of tumor growth modulating activity. The most common tumor types examined included breast, nonsmall cell lung, ovarian, colorectal cancer, and melanoma. Stimulation of tumor colony-forming units (colony formation greater than or equal to 1.5 x controls) was observed in only 1/56 (2%) tumors. No evidence was found for increased size of individual colonies after incubation with rhIL-1 alpha. At a concentration of 100 ng/ml, colony formation of 9/56 (16%) tumor specimens was significantly inhibited (colony formation less than or equal to 0.5 x controls). We conclude that rhIL-1 alpha is not a major modulator of tumor colony formation in vitro. However, some antitumor effects may be observed at high concentrations.

Humans↗
PubMed1990

In vitro assessment of the effects of granulocyte-macrophage colony-stimulating factor on primary human tumors and derived lines.

One hundred eighty-nine human tumor specimens were tested in a human tumor cloning assay to determine their growth response to human recombinant granulocyte-macrophage colony-stimulating factor. Of these samples 48 were evaluable for response. Growth stimulation to greater than 150% of controls was noted in 1 of 12 lung cancers (8%) and 1 of 14 breast cancers (7%) but in no other instances for an overall rate of 2 of 48 (4.2%). A dose-response effect was not seen with each of the two stimulated samples responding only at the two lowest concentrations tested. In addition, 7 cell lines derived from human tumors were tested using a metabolic CO2 production assay without evidence of growth stimulation. Samples of normal bone marrow displayed the usual dose-dependent stimulation whether grown in agar or assayed metabolically. We conclude that human recombinant granulocyte-macrophage colony-stimulating factor has minimal effect on the growth of the solid tumors tested and that clinical trials to reduce chemotherapy-associated myelo-suppression may proceed without undue concern for enhancement of tumor growth.

Adenocarcinoma↗
PubMed1987

Biphasic effect of vanadium salts on in vitro tumor colony growth.

Vanadium is a trace element widely distributed in nature. It interferes with a variety of enzyme systems and is also reported to increase DNA-synthesis and in vitro clonal growth of human and mouse fibroblasts. The purpose of the present study was to determine the effect of vanadium salts on the in vitro growth of fresh human tumor specimens. Various concentrations of ammonium metavanadate (AMV), vanadyl sulfate trihydrate (VST) and ortho sodium vanadate (OSV) were tested in a human tumor cloning assay (HTCA). Thirty-four evaluable specimens were tested at concentrations of less than or equal to 10(-10) M of one or more vanadium salts. At this concentration, colony formation was increased by greater than or equal to 150% as compared to control at one or more concentrations in 16 specimens (47%). Twelve evaluable specimens were tested against various concentrations greater than 10(-10) M. Colony formation was inhibited by greater than or equal to 50% of the control at one or more concentrations in all specimens. In further experiments we performed a head-to-head comparison of OSV (10(-3)M) and our standard positive control for cell kill (chromomycin A3, 100 micrograms/ml) in 34 specimens. OSV led to a comparable or better cell kill in 28 tumors (82%). We conclude that vanadium salts at low concentrations (less than or equal to 10(-10)M) can stimulate in vitro colony formation from human tumors. At higher concentrations (greater than 10(-10)M) tumor colony formation is inhibited. OSV might be useful as a very inexpensive positive control in the HTCA. In addition, the value of vanadium salts as antitumor agents should be further investigated in vivo.

Cell Division↗
PubMed1986

Use of in vitro dose response effects to select antineoplastics for high-dose or regional administration regimens.

Several preclinical and clinical studies have documented that dose or dose intensity of chemotherapeutic agents are important factors for response of patients' tumors. This finding has prompted empiric trials of certain chemotherapeutic agents in high-dose or regional administration treatment regimens. The present study was performed to identify agents that would be particularly good candidates for high-dose or regional administration regimens against particular types of tumors. Using a human tumor cloning technique, we constructed dose in vitro response lines for ten different chemotherapeutic agents against seven different histologic types of malignancies. Slopes of the lines indicated the agents with the greatest increases of in vitro response per increment in dose of the agent. Tumors against which the agents gave the steepest dose response lines included lymphoma, head and neck cancer, ovarian cancer, and small-cell lung cancer, while the dose response lines for non-small-cell lung cancer, breast cancer, and colon cancer were quite flat. Suggestions for clinical trials based on these findings include the use of high-dose melphalan for patients with lymphoma, head and neck, and ovarian cancer; the use of mitoxantrone in high-dose regimens for patients with breast cancer; high-dose cisplatin regimens for patients with small-cell lung cancer; high-dose bleomycin regimens for patients with non-small-cell lung and head and neck cancer; and regional perfusion of liver metastases from colorectal cancer with cisplatin. Prospective testing of high-dose or regional administration regimens suggested by this new model should indicate its use for prediction of the best agent to use in high-dose regimens against a particular tumor type.

Antineoplastic Agents↗
PubMed1978

Anorexia nervosa: dietary treatment and re-establishment of body weight in 20 cases studied on a metabolic unit.

This paper reviews the nutritional treatment and weight progress of 20 patients with anorexia nervosa studied in a teaching hospital metabolic unit between January 1974 and August 1977. The classification of patients, their pre-admission dietary intakes and weight status are compared. The method of re-establishing weight by closely monitored normal nutrition under conditions of bedrest and chlorpromazine medication are described. It is illustrated by the progress of one 14-year-old girl patient and the study of the rate of increase in weight of the whole group. Satisfactory weight levels were attained by all patients with acceptable time limits.

Adolescent↗