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Biomedical subjects

S Rockwell

Publications and source records attributed to S Rockwell.

At least 37 records · Page 2Linked to original sources
PubMed1998

RSR13, a synthetic allosteric modifier of hemoglobin, as an adjunct to radiotherapy: preliminary studies with EMT6 cells and tumors and normal tissues in mice.

RSR13, 2[4-[[(3,5dimethylanilino)carbonyl]methyl]phenoxy]-2-methylpropion ic acid, a synthetic allosteric modifier of hemoglobin, reduces the affinity of hemoglobin for oxygen. The experiments reported here examined the effect of treatment with RSR13, combined with oxygen breathing, on the radiation response of EMT6 mammary tumors in BALB/c mice and of two normal tissues. RSR13 plus oxygen breathing increased the response of EMT6 tumors to irradiation. RSR13 had no discernible effects on tumors rendered maximally hypoxic by nitrogen asphyxiation, no discernible cytotoxic effects in EMT6 tumors, and no effect on the viability or radiation response of EMT6 cells in vitro under either aerobic or hypoxic conditions. The effects of RSR13 therefore reflect changes in tumor oxygenation, rather than a direct cytotoxic or radiosensitizing effect of the drug. RSR13 plus oxygen reduced the hypoxic fraction to 9% from the value of 24% found in both air-breathing and oxygen-breathing mice. Treatment with RSR13 plus oxygen did not alter the radiation response of the bone marrow progenitor cells (CFU-S) or acute radiation reactions in the skin. The improvement in tumor radiation response produced by treatment with RSR13 plus oxygen, combined with the absence of enhanced radiation reactions in the normal tissues, support further testing of RSR13 as an adjunct to radiotherapy.

Aniline Compounds↗
PubMed1998

Exploring the mechanistic aspects of mitomycin antibiotic bioactivation in Chinese hamster ovary cells overexpressing NADPH:cytochrome C (P-450) reductase and DT-diaphorase.

We have directly demonstrated the involvement of human NADPH: cytochrome c (P-450) reductase in the aerobic/hypoxic differential toxicity of mitomycin C and porfiromycin in living cells by varying only this enzyme in a transfected cell line. In the same manner, we have implicated rat DT-diaphorase in the aerobic and hypoxic activation of mitomycin C, but found only a minor role for this enzyme in the aerobic activation of porfiromycin. DT-Diaphorase does not cause the production of an aerobic/hypoxic differential toxicity by mitomycin C, but rather activates this agent through an oxygen insensitive pathway. The evidence suggests that DT-diaphorase activates mitomycin C more effectively than porfiromycin, with porfiromycin being preferentially activated through a one-electron reductive pathway. The therapeutic potential of mitomycin antibiotics in the treatment of cancer can be envisioned to be enhanced for those tumors containing elevated levels of the bioreductive enzymes. However, cytogenetic heterogeneity within the tumor cell population and the various environmental factors which impact on bioreductive enzyme function, including pH and oxygen tension, may subvert this approach. Moreover, if high tumor levels of a drug activating enzyme reflect high levels in the normal tissues of the patient, normal tissue damage may also be enhanced with possibly no improvement in the therapeutic ratio. Approaches utilizing gene therapy, whereby a specific bioreductive catalyst is introduced into the tumor cell population via a targeting vehicle to activate a particular prodrug, may be more effective in that not only will the prodrug of choice be specifically activated in the tumor, but the source of the catalyst, be it bacterial, rodent, or human, will not be important. In fact, in the case of DT-diaphorase and mitomycin C, the rat form of the enzyme could be advantageous because it is more effective in activating mitomycin C than is the human form of this enzyme. Assuming targeted gene delivery to malignant cells, a non-host enzyme which is more effective at activating mitomycin C than the analogous host enzyme might also result in less drug activation in normal tissue and, hence, less normal tissue toxicity.

Animals↗
PubMed1998

Vitamin A inhibits radiation-induced pneumonitis in rats.

Radiation-induced lung injury frequently limits the total dose of thoracic radiotherapy that can be delivered, and the determinants of host susceptibility are poorly understood. To test the hypothesis that vitamin A status may be an important, modifiable host determinant of radiation-induced lung injury, we determined the effect of altered vitamin A status on radiation-induced lung inflammation in rats. WAG-Rij Y rats were fed a diet deficient in or supplemented with vitamin A (0 units/kg or 80,000 units/kg diet). After 5 wk of consuming the prescribed diet, rats were irradiated with 15 Gy of 250 kV X-rays to the whole thorax. At 4-5 wk post-irradiation, there were significantly fewer neutrophils on bronchoalveolar lavage in rats fed the vitamin A-supplemented diet (8.8 +/- 1.2% neutrophils) compared with those fed the vitamin A-deficient diet (20.8 +/- 3.4% neutrophils, P < 0.01). At the termination of the experiment, 4-5 wk postradiation, lung retinol levels of the vitamin A-supplemented group were 19.6 +/- 1.8 nmol/g, whereas those in the vitamin A-deficient group were significantly lower, 1.7 +/- 0.5 nmol/g (P < 0.01). These findings suggest that supplemental vitamin A may reduce lung inflammation after thoracic radiation and be an important modifiable radioprotective agent in the lung.

Animals↗
PubMed1998

Formation of a major DNA adduct of the mitomycin metabolite 2,7-diaminomitosene in EMT6 mouse mammary tumor cells treated with mitomycin C.

Treatment of EMT6 mouse mammary tumor cells with [3H]mitomycin C (MC) results in the formation of six major DNA adducts, as described earlier using an HPLC assay of 3H-labeled products of enzymatic hydrolysis of DNA isolated from MC-treated cells. Four of these adducts were identified as monofunctional and bifunctional guanine-N2 adducts in the minor groove of DNA. In order to establish relationships between individual types of MC-DNA adducts and biological responses it is necessary to identify all of the adducts formed in cells. To this end we have now identified a predominant, previously unknown adduct formed in MC-treated EMT6 cells as a derivative not of MC, but of 2,7-diaminomitosene (2,7-DAM), the major bioreductive metabolite of MC. Rigorous proof demonstrates that it is a DNA major groove, guanine-N7 adduct of 2,7-DAM, linked at C-10 to DNA. The adduct is relatively stable at ambient temperature, but is readily depurinated upon heating. Its isolation from MC-treated cells indicates that MC is reductively metabolized to 2,7-DAM, which then undergoes further reductive activation to alkylate DNA, along with the parent MC. Low MC:DNA ratios were identified as a critical factor promoting 2,7-DAM adduct formation in an in vitro model calf thymus DNA/ MC/reductase model system, as well as in MC-treated EMT6 cells. The 2,7-DAM-guanine-N7 DNA adduct appears to be relatively noncytotoxic, as indicated by the dramatically lower cytotoxicity of 2,7-DAM in comparison with MC in EMT6 cells. Like MC, 2,7-DAM exhibited slightly greater cytotoxicity to cells treated under hypoxic as compared to aerobic conditions. However, 2,7-DAM was markedly less cytotoxic than MC under both aerobic and hypoxic conditions. Thus, metabolic reduction of MC to 2,7-DAM represents a detoxification process. The differential effects of MC-DNA and 2,7-DAM-DNA adducts support the concept that specific structural features of the DNA damage may play a critical role in the cytotoxic response to a DNA-targeted chemotherapeutic agent.

Animals↗
PubMed1998

Experimental radiotherapy: a brief history.

Studies of the effects of ionizing radiation on tumors and normal tissues began within weeks of Roentgen's discovery of X rays, and are continuing today. The evolution of these studies reflects both the changing philosophy and sociology of science and the continuing application of new technologies and new knowledge from a diverse range of scientific fields to address the important problem of improving the treatment of cancer. This brief history reviews the evolution of "experimental radiotherapy" over the past century and describes how the development of new technologies and new experimental models influenced this field of study. In addition, it describes critical points at which studies in radiation biology and cancer biology had an impact on research throughout the biomedical sciences.

Animals↗
PubMed1997

Bioreductive alkylating agent porfiromycin in combination with radiation therapy for the management of squamous cell carcinoma of the head and neck.

Porfiromycin (methyl mitomycin C) has been shown in laboratory studies to have increased preferential cytotoxicity to hypoxic cells and therefore may provide enhanced therapeutic efficacy over mitomycin C when used in combination with radiation therapy (RT). The purpose of the two clinical studies reported here is to evaluate the concomitant use of porfiromycin with RT in the management of squamous cell carcinoma of the head and neck. Between October 1989 and July 1992, 21 patients presenting with locally advanced stage III/IV squamous cell carcinoma of the head and neck were entered into a phase I toxicity trial evaluating porfiromycin as an adjunct to RT. Patients were eligible if they had biopsy documented squamous cell carcinoma of the head and neck with a low probability of cure by conventional means. Patients were treated with standard fractionated daily RT to a total median dose of 63 Gy, with porfiromycin administered on days 5 and 47 of the course of RT. Upon completion of this phase I trial, a phase III trial was initiated in November 1992 randomizing patients with squamous cell carcinoma of the head and neck to RT with mitomycin C vs. RT with porfiromycin. There is no radiation only arm in this current trial. To date, 75 patients have been entered on this trial and acute toxicity data are available on 67 patients (34 porfiromycin, 31 mitomycin C) who have completed their entire course of treatment. Median follow-up of the 21 patients enrolled in the phase I porfiromycin trial is 58.5 months. Of the 21 patients, 5 were treated at a dose of 50 mg/M2, 4 at 45 mg/M2, and the final 12 at 40 mg/M2, which appeared to result in acceptable acute hematological and nonhematological toxicities. As of December 1995, 14 of the 21 patients have died with disease and 7 remain alive and free of disease, resulting in a 5-year actuarial survival of 32%. Of the patients enrolled to date in the phase III randomized trial of mitomycin C vs. porfiromycin, there have been no statistically significant differences between the two arms with respect to white blood cell count (WBC), platelet, or hemoglobin nadirs. Acute nonhematological toxicities including mucositis, epidermitis, odynophagia, and nausea have also been comparable. Two patients in this current randomized trial died during treatment, apparently of nondrug-related causes. We conclude that the bioreductive alkylating agent porfiromycin has demonstrated an acceptable toxicity profile to date. Final analysis of the phase I trial, which revealed a 5-year no evidence of disease survival rate of 32% in patients with locally advanced disease and a low probability of cure, appears encouraging. We anticipate completion of the current ongoing trial comparing mitomycin C to porfiromycin in the next 2 years. Further investigations, including large-scale multiinstitutional trials employing bioreductive alkylating agents or other hypoxic cell cytotoxins as adjuncts to RT, are warranted.

Antibiotics, Antineoplastic↗
PubMed1997

Chemotherapy as an adjunct to radiation in the treatment of squamous cell carcinoma of the head and neck: results of the Yale Mitomycin Randomized Trials.

PURPOSE: Two consecutive randomized trials were run at our institution using the bioreductive alkylating agent mitomycin as an adjunct to radiation therapy in an effort to improve outcome in patients with squamous cell carcinoma of the head and neck. METHODS: Between 1980 and 1992, two consecutive randomized trials using mitomycin (trial 1) and mitomycin with dicumarol (trial 2) as an adjunct to radiation therapy in patients with squamous cell carcinoma of the head and neck were conducted at our institution. The patients were stratified by intent of therapy, extent of disease, and primary tumor site. Within each strata, patients were randomized to receive radiation therapy with or without mitomycin (trial 1) or mitomycin/dicumarol (trial 2). RESULTS: A total of 203 patients were enrolled onto both trials, 195 of whom were eligible for analysis. Patients were equally balanced with respect to sex, age, extent of disease, primary site, radiation dose, and total duration of radiation treatment. Hematologic toxicities were more frequently noted in the drug-treated arms, but were acceptable with no drug-related treatment deaths. Nonhematologic toxicities were acceptable and not significantly different between the two arms. As of September 1995, with a median follow-up of 138 months, a statistically significant benefit occurred in the mitomycin arms with respect to cause-specific survival (0.74 +/- 0.05 v 0.51 +/- 0.05; P = .005), local recurrence-free survival (0.85 +/- 0.04 v 0.66 +/- 0.05; P = .002), and local regional recurrence-free survival (0.76 +/- 0.05 v 0.54 +/- 0.05; P = .003). No statistically significant difference in overall survival was obtained (0.48 +/- 0.05 mitomycin arms v 0.42 +/- 0.05 radiation alone). CONCLUSION: The bioreductive alkylating agent mitomycin is a safe and effective adjunct to radiation therapy in the treatment of squamous cell carcinoma of the head and neck. The statistically and clinically significant improvement in local regional relapse and cause-specific survival obtained support the use of mitomycin as an adjunct to radiation therapy in the management of squamous cell carcinoma of the head and neck.

Adult↗
PubMed1997

Oxygen delivery: implications for the biology and therapy of solid tumors.

Solid malignancies develop areas of hypoxia during the earliest phase of their development, while they are still microscopic in size and before they have initiated angiogenesis. The physiologic effects of hypoxia and the associated microenvironmental inadequacies increase mutation rates, select for cells deficient in normal pathways of programmed cell death, and contribute to the development of an increasingly invasive, metastatic phenotype. Hypoxic tumor cells are also resistant to radiation and to many antineoplastic drugs, and can limit the curability of solid tumors by radiotherapy and chemotherapy. This article reviews several approaches to improving tumor oxygenation and discusses the results of laboratory and clinical studies examining their efficacy in improving the outcome of radiation therapy. Past clinical trials, using nonoptimal agents and regimens to circumvent the protective effects of hypoxia, improved local control rates by approximately 10%. Greater improvements should be possible when the new agents now undergoing laboratory testing are used in optimally designed clinical regimens.

Antineoplastic Agents↗
PubMed1996

Independent regulation of invasion and anchorage-independent growth by different autophosphorylation sites of the macrophage colony-stimulating factor 1 receptor.

Invasion of tissue by macrophages and implantation into the uterine wall by placental trophoblasts are known to be regulated by the macrophage colony-stimulating factor (CSF-1) and its receptor (CSF-1R, the product of the c-fms proto-oncogene). Recently, the clinical importance of CSF-1 and CSF-1R in invasive breast carcinoma has been recognized, but the significance of coexpression of CSF-1 and CSF-1R in mammary epithelial cell invasion has not been explored. In the present study, we investigated the invasive potential of a noninvasive, CSF-1R-negative, mouse mammary epithelial cell line (HC11) expressing a high level of CSF-1, which was stably transfected with the mouse wild-type CSF-1R. Compared with parental cells, transfected cells expressing a wild-type CSF-1R invaded 100-fold more efficiently through a barrier of reconstituted basement membrane (Matrigel) and formed colonies in soft agar, whereas the cellular growth rate was only slightly increased. Analysis of cell-conditioned medium by zymography and quantitative enzyme activity assays showed that clones transfected with a wild-type CSF-1R expressed significantly higher levels of urokinase-type plasminogen activator than did untransfected clones. Furthermore, after injection into the tail veins of BALB/c mice, CSF-1R-expressing clones also produced a 10-fold higher incidence of lung tumors than the parental cell line. We also analyzed HC11 clones transfected with CSF-1R mutated at two major autophosphorylation sites (Tyr-->Phe807 and Tyr-->Phe721). Mutation at Tyr807 eradicated the stimulatory effect of Fms expression on the invasive ability of HC11 cells and substantially reduced the metastatic potential of the transfected clones but did not alter the Fms-induced anchorage-independent growth in soft agar. In contrast, mutation at Tyr721 of Fms had no effect on invasion as measured in the in vitro assay but markedly abolished Fms-induced colony formation in soft agar and eradicated the metastatic potential of the transfected clones. Our results suggest that expression of CSF-1R can facilitate cellular invasion and anchorage-independent growth in mammary epithelial cells, and these two processes are independently regulated by separate phosphotyrosine sites of CSF-1R.

3T3 Cells↗
PubMed1996

Genetic instability induced by the tumor microenvironment.

The tumor microenvironment is characterized by regions of fluctuating hypoxia, low pH, and nutrient deprivation. To determine the genetic consequences of growth under these conditions, we used a tumorigenic cell line carrying a recoverable, chromosomally based lambda phage shuttle vector designed to report mutations without the need for genetic selection of mutant cells. The cells were grown in parallel either in culture or as tumors in nude mice. The frequency of mutations arising in cells within the tumors was found to be 5-fold higher than that in otherwise identical cells grown in culture. A distinct pattern of mutation was also seen, with significantly more deletions and transversions in the tumors than in the cell cultures. Furthermore, exposure of the cultured cells to hypoxia produced an elevated mutation frequency and a mutation pattern similar to that seen in the tumors. These results indicate that the conditions within solid tumors are mutagenic and suggest that a fundamental mechanism of tumor progression in vivo is genetic instability induced by the tumor microenvironment.

Animals↗
PubMed1996

IL-11 enhances survival and decreases TNF production after radiation-induced thoracic injury.

We hypothesized that IL-11 would protect against radiation-induced thoracic injury. To test this hypothesis, we compared the survival of rIL-11 and vehicle-treated control mice after 25 Gy of thoracic irradiation, and initiated studies to elucidate the mechanism of the observed protection. This dose of radiation killed 50% of the control mice during the first 2 wk after irradiation. In contrast, the s.c. administration of rIL-11 resulted in significant radioprotection with 89% of the rIL-11-treated animals surviving the study interval (p < 0.001). This radioprotection was at least partially specific for normal thoracic structures since rIL-11 did not alter the development or radiosensitivity of EMT6 tumor cells growing as lung metastases. TNF mRNA was not detected in normal lungs but was impressively induced after thoracic irradiation. Treatment with rIL-11 abrogated this increase. Parallel in vitro studies demonstrated that rIL-11 inhibits LPS and radiation-induced macrophage TNF protein production and mRNA accumulation. These studies demonstrate that rIL-11 reduces the mortality following thoracic irradiation, without enhancing the development or diminishing the radiosensitivity of pulmonary metastatic tumors. They also demonstrate that rIL-11 inhibits both radiation-induced TNF mRNA expression in vivo and macrophage TNF protein production and mRNA accumulation in vitro, suggesting that the radioprotective effects of rIL-11 may be mediated, at least in part, via the modulation of TNF production.

Animals↗
PubMed1996

The immunophilin FKBP12 functions as a common inhibitor of the TGF beta family type I receptors.

The immunophilin FKBP12 is an evolutionarily conserved abundant protein; however, its physiological roles remain poorly defined. Here we report that FKBP12 is a common cytoplasmic interactor of TGF beta family type I receptors. FKBP12 binds to ligand-free TGF beta type I receptor, from which it is released upon a ligand-induced, type II receptor mediated phosphorylation of the type I receptor. Blocking FKBP12/type I receptor interaction with FK506 nonfunctional derivatives enhances the ligand activity, indicating that FKBP12 binding is inhibitory to the signaling pathways of the TGF beta family ligands. Overexpression of a myristylated FKBP12 in Mv1Lu cell specifically inhibits two separate pathways activated by TGF beta, and two point mutations on FKBP12 (G89P, I90K) abolish the inhibitory activity of FKBP12, suggesting that FKBP12 may dock a cytoplasmic protein to the type I receptors to inhibit TGF beta family mediated signaling.

Activin Receptors, Type I↗
PubMed1996

Bioactivation of mitomycin antibiotics by aerobic and hypoxic Chinese hamster ovary cells overexpressing DT-diaphorase.

DT-Diaphorase catalyzes a two-electron reduction of mitomycin C (MC) and porfiromycin (POR) to reactive species. Many cell lines that overexpress DT-diaphorase and are sensitive to the mitomycins are protected from the aerobic cytotoxicity of these drugs by the DT-diaphorase inhibitor dicumarol. The cytoprotective properties of this relatively non-specific inhibitor, however, vanish under hypoxic conditions. To ascertain the role of DT-diaphorase in mitomycin bioactivation and cytotoxicity in living cells, a rat liver DT-diaphorase cDNA was transfected into Chinese hamster ovary cells. MC was equitoxic to the parental cells under oxygenated and hypoxic conditions. In contrast, POR was less toxic than MC to these cells under aerobic conditions, but significantly more toxic than MC under hypoxia. Two DT-diaphorase-transfected clones displayed increases in DT-diaphorase activity of 126- and 133-fold over parental cells. The activities of other oxidoreductases implicated in mitomycin bioreduction were unchanged. MC was more toxic to both DT-diaphorase-transfected lines than to parental cells; the toxicity of MC to the transfected lines was similar in air and hypoxia. POR was also more toxic to the DT-diaphorase-elevated clones than to parental cells under oxygenated conditions. Under hypoxia, however, the toxicity of POR to the transfected clones was unchanged from that of parental cells. The findings implicate DT-diaphorase in mitomycin bioactivation in living cells, but suggest that this enzyme does not contribute to the differential toxicity of MC or POR in air and hypoxia.

Animals↗
PubMed1996

Differential toxicity of mitomycin C and porfiromycin to aerobic and hypoxic Chinese hamster ovary cells overexpressing human NADPH:cytochrome c (P-450) reductase.

Purified NADPH:cytochrome c (P-450) reductase (FpT; NADPH-ferrihemoprotein oxidoreductase, EC 1.6.2.4) can reductively activate mitomycin antibiotics through a one-electron reduction to species that alkylate DNA. To assess the involvement of FpT in the intracellular activation of the mitomycins, transfectants overexpressing a human FpT cDNA were established from a Chinese hamster ovary cell line deficient in dihydrofolate reductase (CHO-K1/dhfr-). The parental cell line was equisensitive to the cytotoxic action of mitomycin C under oxygenated and hypoxic conditions. In contrast, porfiromycin was considerably less cytotoxic to wild-type parental cells than was mitomycin C in air and markedly more cytotoxic under hypoxia. Two FpT-transfected clones were selected that expressed 19- and 27-fold more FpT activity than the parental line. Levels of other oxidoreductases implicated in the activation of the mitomycins were unchanged. Significant increases in sensitivity to mitomycin C and porfiromycin in the two FpT-transfected clones were seen under both oxygenated and hypoxic conditions, with the increases in toxicity being greater under hypoxia than in air. These findings demonstrate that FpT can bioreductively activate the mitomycins in living cells and implicate FpT in the differential aerobic/hypoxic toxicity of the mitomycins.

Aerobiosis↗
PubMed1996

Interactions of BMS-181174 and radiation: studies with EMT6 cells in vitro and in solid tumors.

N-7[2-(4-nitrophenyldithio)-ethyl] mitomycin C, (BMS-181174; previously designated as BMY25067) is a mitomycin C analog now in initial clinical trials. The experiments described in this report were performed to assess whether BMS-181174, like mitomycin C and porfiromycin, was selectively toxic to the hypoxic cells in solid tumors and might therefore prove valuable in combination with radiotherapy. In contrast to mitomycin C and porfiromycin, BMS-181174 was more toxic to aerobic EMT6 cells in vitro than to cells made acutely hypoxic. In vitro, BMS-181174 and radiation produced cytotoxicity compatible with either additive or slightly supra-additive cytotoxicity. In vivo, BMS-181174 was effective in killing cells in solid EMT6 tumors. The effects of regimens combining BMS-181174 and radiation in vivo were complex. Combinations of low doses of BMS-181174 plus a large dose of radiation were very effective in killing cells in solid tumors. However, the survival curve plateaued at high doses of BMS-181174, providing evidence for a subpopulation of tumor cells which were resistant to both BMS-181174 and radiation; this was hypothesized to be a hypoxic cell population.

Aerobiosis↗
PubMed1996

Hearing what cannot be seen: a psychoanalytic research group's inquiry into female sexuality.

Advances in the theoretical understanding of female psychology are not easily integrated into psychoanalytic practice. This paper reports on a study of female psychology and clinical practice by a group of seven female psychoanalysts. Through discussing the literature and case vignettes, we discovered a lag between current theoretical ideas and our clinical practice. The group identified an anachronistic emphasis on penis envy functioning as "bedrock." This report addresses how the group facilitated individual members' integration of theory and practice, and how this integration affected work with patients. We found that as we became open to considering a wider range of potential dynamic meanings of penis envy and female bodily concerns, we were able to explore a richer, and often surprising unfolding of vicissitudes. The discussion highlights some technical issues with this approach.

Fantasy↗
PubMed1995

Cytotoxicity of BMS-181174. Effects of hypoxia, dicoumarol, and repair deficits.

The mitomycin C (MC) analog BMS-181174 (previously designated as BMY25067) has been shown to be active against a variety of solid tumors in mice. The activity of this compound against tumor cell lines resistant to MC and the different toxicity profiles of BMS-181174 and MC suggested that there may be significant differences in the metabolism and the mechanisms of action of these two compounds. Our studies with a mouse mammary tumor cell line (EMT6), a wild-type Chinese hamster cell line (AA8), and three repair-deficient Chinese hamster cell lines (UV4, UV5, and EM9) supported this concept. BMS-181174 was more toxic to all five cell lines in air than in hypoxia; in contrast, MC is more toxic in hypoxia. Dicoumarol (which increases the cytotoxicity of MC in hypoxia and reduces the cytotoxicity of this drug in air) did not alter the cytotoxicity of BMS-181174. This finding suggests that neither DT-diaphorase nor cytochrome b5 reductase is involved in the activation of BMS-181174. Studies with the repair-deficient cell lines suggest that DNA strand breaks are not important to the cytotoxicity of BMS-181174, and that cross-links and adducts may be the critical lesions; these studies also suggest that the lethal lesions produced by BMS-181174 are the same under aerobic and hypoxic conditions.

Animals↗