Biomedical subjects

R T Dorr

Publications and source records attributed to R T Dorr.

At least 109 records · Page 6Linked to original sources

PubMed1988

Direct relation of DNA lesions in multidrug-resistant human myeloma cells to intracellular doxorubicin concentration.

Using a human myeloma cell line selected for resistance to doxorubicin (8226/DOX), which expresses the multidrug resistance phenotype, we studied the effects of drug accumulation on DNA damage and cytotoxicity in multidrug-resistant cells. The resistant 8226 subline showed a decrease in [14C]doxorubicin accumulation as compared to the sensitive (8226/S) subline at all time points investigated. DNA alkaline elution techniques were used to examine the formation of single and double strand breaks and DNA-protein cross-links following exposure to doxorubicin in both sensitive and resistant sublines. When 8226/S and 8226/DOX40 cells were exposed to the same extracellular concentration of doxorubicin there was a difference in the quantity of DNA lesions occurring, with the 8226/DOX40 line exhibiting less DNA damage. However, when the extracellular concentration of drug was adjusted to yield equivalent intracellular concentrations these differences were removed and both lines exhibited the same degree of damage for all three DNA lesions. The same DNA lesions were also studied in isolated nuclei from sensitive and resistant cells. Such a model removes any confounding factors due to drug accumulation such as altered cytosolic distribution and/or metabolism of drug. We observed no difference in the formation of single or double strand breaks, or DNA-protein cross-links when the nuclei were exposed to the same concentration of doxorubicin. Results from colony-forming assays have shown that when resistant and sensitive 8226 cells were exposed to high concentrations of doxorubicin, there was a good correlation between DNA damage, drug accumulation, and cytotoxicity. This relationship did not hold for lower concentrations of doxorubicin, for which there was a lack of correlation between drug accumulation and cytotoxicity. Such findings may possibly be due to a prolonged retention of drug by the sensitive cell line as compared to the resistant cells. Further studies are under way to examine this possibility.

Cell Survival↗

PubMed1988

Verapamil reversal of doxorubicin resistance in multidrug-resistant human myeloma cells and association with drug accumulation and DNA damage.

Verapamil reversed resistance to doxorubicin in a human multiple myeloma cell line selected for multiple drug resistance. The drug-resistant cell line 8226/DOX40 is known to have reduced intracellular drug accumulation associated with the overexpression of P-glycoprotein when compared to the sensitive parent cell line 8226/S. Verapamil alone was minimally cytotoxic in both cell lines, but reversed doxorubicin resistance in a dose-related manner in 8226/DOX40. A similar dose-response relationship was observed for verapamil in increasing net intracellular doxorubicin accumulation. This increased net accumulation was secondary to block of enhanced doxorubicin efflux by verapamil from resistant cells. In contrast, verapamil did not alter initial doxorubicin accumulation over the first 60 s when incubated with resistant cells. Addition of verapamil to the 8226/DOX40 cells enhanced the formation of doxorubicin-induced DNA single strand breaks, double strand breaks, and DNA-protein cross-links. Verapamil had no effect on these lesions in the drug-sensitive cells. In addition, verapamil did not affect chemotherapeutic cytotoxicity or transport in the drug-sensitive cell line. Verapamil appears to reverse doxorubicin resistance in this human myeloma cell line by blocking enhanced drug efflux, leading to increased drug accumulation and enhanced DNA damage.

Cell Survival↗

PubMed1988

In vitro rat myocyte cardiotoxicity model for antitumor antibiotics using adenosine triphosphate/protein ratios.

Cumulative cardiotoxicity consistently limits the use of antitumor anthracyclines such as doxorubicin (DOX). Several in vivo and in vitro model systems have been developed for screening cardiotoxic agents. Problems with these models include excessive time and nonquantitative toxicity end points. We describe an in vitro system for culturing cardiac myocytes which overcomes these problems. Optimal myocyte cultures were obtained using serial 0.2% crude trypsin digestions of hearts from 1-2-day-old rats. Three-day-old myocyte cultures were treated with DOX for 6 h at concentrations of 0.1 to 10 micrograms/ml (0.18 to 18 microM). Electron microscopy performed on control and DOX-treated cultures showed characteristic histopathological signs of anthracycline damage. These changes included mitochondrial swelling, nuclear pleomorphism, chromatin clumping, and a diffuse loss of membrane integrity. Intracellular ATP, quantitated by the luciferase bioluminescence method, was shown to provide a simple and consistent quantitative biochemical marker of myocyte viability over the range of DOX concentrations used. The results showed both time- and dose-dependent decrements in ATP/protein ratios 72 h following exposure to DOX at concentrations greater than 0.1 microgram/ml. Leakage of lactate dehydrogenase activity, trypan blue uptake, and myocyte beating rates were variable and not as sensitive as ATP levels for evaluation of myocyte viability. Other cytotoxic agents which are not known to be cardiotoxic (dactinomycin, 1-beta-D-arabinofuranosylcytosine, fluorouracil, melphalan, and vincristine), required extremely high concentrations to produce myocyte damage in vitro. Tests with anthracycline analogues also demonstrated the ability of the assay to rank-order cardiotoxic agents on a weight basis: idarubicin greater than DOX greater than daunomycin greater than aclarubicin. When the in vitro drug concentrations required to lower ATP/protein ratios to 50% of controls were related to clinically achievable concentration x time products, DOX and daunomycin proved to be the most cardiotoxic in this series. These results suggest that comparative cardiotoxic screening studies may be performed in vitro using ATP levels in beating neonatal myocytes.

Adenosine Triphosphate↗

PubMed1988

Toxicologic studies of a superpotent alpha-melanotropin, [Nle4, D-Phe7]alpha-MSH.

A toxicology study was performed in mice given a superpotent alpha melanocyte stimulating hormone (MSH) analog. This 13 amino acid derivative, [Nle4, D-Phe7]alpha-MSH or NDP-MSH, is a melanotropin which is very slowly biodegraded in vivo and is active at 1/1,000 the concentration of natural alpha-MSH. Mice were administered up to 2 mg/kg of the analog daily and weekly over 4 or 12 weeks by both topical application (in 90% DMSO) or by IP injections (in physiologic saline). At the end of this period, no toxic effects were observed in various organs, on hematologic indices, or on weight gain. A slight increase in triglyceride and platelet levels were noted in mice given the analog weekly for 12 weeks. There was no evidence of an effect on behavior nor ACTH-like endocrine actions such as elevated serum cortisol levels. Transdermal drug delivery studies performed in vitro showed reproducible diffusion of the NDP-MSH analog through full-thickness mouse skin. Approximately 0.002% to 0.05% of a 10(-4) M preparation was transdermally delivered using a DMSO/water solution or a PEG/alcohol cream base, respectively. This superpotent analog is now entering a Phase I clinical trial with possible therapeutic applications for the treatment of hypomelanotic disorders such as vitiligo and for pharmacologic tanning without the need for sunlight exposure.

Administration, Cutaneous↗

PubMed1988

Efficacy of sodium thiosulfate as a local antidote to mechlorethamine skin toxicity in the mouse.

The highly vesicant nature of the alkylating anticancer agent mechlorethamine (HN2, or nitrogen mustard) requires careful i.v. technique during its administration. Skin toxicity due to HN2 extravasation is severe and typically prolonged over several months. Mouse skin toxicity studies were carried out to find a local antidote to decrease the severity of tissue damage by this agent. Intradermal (i.d.) HN2 (0.005-0.5 mg) caused dose-dependent skin ulcers in the mouse. Isotonic sodium thiosulfate Na2S2O3 (0.167 M) or hypertonic (0.34 M) Na2S2O3 (0.05 ml) given immediately after HN2 significantly reduced the mean HN2 ulceration area and the total time of ulceration. Ineffective local HN2 antidotes included hyaluronidase, hydrocortisone, and sodium chloride, all given i.d. Topical applications of DMSO, cold, and heat were also ineffective. Sodium thiosulfate is believed to chemically neutralize reactive mechlorethamine-alkylating species and thus decrease skin toxicity. Thiosulfate dosing studies showed that a molar excess of at least 200:1 (Na2S2O3:HN2) was required for significant antidotal activity. If thiosulfate treatment was delayed 4-24 h after HN2, no antidotal effects were obtained. We conclude that sodium thiosulfate can decrease the severity of local tissue damage caused by HN2. It should be considered the antidote of choice in the setting of clinical HN2 extravasations.

Animals↗

PubMed1988

Cimetidine enhances cisplatin toxicity in mice.

The combination of the histamine H2 antagonist cimetidine (CMT) and the anticancer agent cisplatin (CDDP) was studied in normal and tumorbearing mice. CMT doses of 100 mg/kg produced no alteration in the survival of DBA/2J mice bearing P388 leukemia treated with CDDP doses of 3 mg/kg or 6 mg/kg. In these groups, the median survival was 13 days and 16 days, respectively, compared to 10 days in untreated controls. However, when adult CD-1 mice were given higher but nonlethal CDDP doses of 10, 15, or 18 mg/kg, the addition of CMT significantly increased CDDP lethality (P less than 0.05 by Wilcoxon analysis). For the 3 groups, CMT-enhanced lethality occurred in 10% of mice given 10 mg/kg CDDP, 80% of mice given 15 mg/kg, and 100% of mice given 18 mg/kg CDDP. Thus, CMT can acutely alter CDDP toxicity without affecting antitumor efficacy in mice.

Animals↗

PubMed1988

Quantitation of ellipsoid tumor areas using a circumferential measuring device.

A controlled trial of a new circumferential area measuring device, the Tumorimeter, was performed on a set of 30 radiographs of chest nodules ranging in size from 1.5 to 5.0 cm diameter. The Tumorimeter is a hand-held device with a sliding radiolucent loop used to circumferentially measure ellipsoid tumors. It is calibrated in cm2 of surface area. In a crossover comparison with standard Vernier-type calipers, the Tumorimeter was significantly more accurate than bidimensional caliper determinations (less than or equal to 5% surface area error vs a 21-28% overestimate error for calipers). It was also more rapid (an average of 10.5 sec for the Tumorimeter vs 22.3 sec for calipers for each measurement). Both results were statistically significant, P less than 0.0001 by analysis of variance. This trial demonstrates that enhanced speed and accuracy in tumor measurement are possible by using ellipsoid assessments of radiographs. A prospective clinical trial is planned to compare rectangular areas obtained using bidimensional tumor widths, with ellipsoid areas obtained by circumferential tumor measurements using the Tumorimeter.

Equipment and Supplies↗

PubMed1988

Transdermal delivery of a melanotropic peptide hormone analogue.

We previously reported that topical application of [Nle4,D-Phe7]alpha-MSH, a superpotent analogue of alpha-melanocyte stimulating hormone, to mice induces a darkening of follicular melanocytes throughout the skin. We now report that the melanotropin analogue can be delivered across mouse but not rat skin in an in vitro model system. Passage of the analogue from the topically applied vehicle (polyethylene glycol) across the skin into a subcutaneous receiving vessel was demonstrated by both bioassay as well as by radioimmunoassay. The bioassay data demonstrate that percutaneous absorption of the melanotropin did not result in loss of biological activity of the peptide. The differential penetration of the peptide across rodent skin reveals that one cannot predict percutaneous absorption of a substance across the stratum corneum from studies on a single species. The present results are the first to demonstrate, by direct quantitative measurements, that a bioactive peptide can be delivered across the vertebrate integument in vitro. These studies point out the potential of a topically applied melanotropin for tanning of the skin and possibly for treatment of certain hypopigmentary disorders.

Administration, Cutaneous↗

PubMed1988

Daily variation in non-protein sulfhydryl levels of human bone marrow.

There is increasing evidence that the dosing of certain antineoplastic agents based on a circadian type of schedule may have a beneficial effect on the outcome of patient therapy. Such regimens allow for a more intensive course of drugs to be administered due to a reduction in the toxicities associated with these agents. Since many of the antineoplastics in use today either form reactive intermediates or generate toxic free radical species within the cell, cellular thiols such as glutathione may play a role in their detoxification. Our studies were designed to investigate whether there exists a consistent daily fluctuation in the thiol content in human bone marrow samples. Five normal male volunteers, ages 26-32 years, underwent repeat bone marrow aspirations at approx. 8 a.m. and 8 p.m. Mean peak non-protein sulfhydryl (NPSH) levels of 47.7 nmole/mg protein occurred in morning bone marrow aspirates while evening aspirates showed markedly reduced mean levels of 7.9 nmole/mg protein. Reduced glutathione was used as a standard in these assays which measured sulfhydryls spectrophotometrically using Ellman's reagent. Our findings may help to explain the observed reduction in myelotoxicity in chemotherapy designed to take advantage of human circadian rhythms. These results support the proposition that the administration of certain cytotoxic drugs to match peak levels of thiols in the marrow may facilitate more intensive and active chemotherapy regimens.

Adult↗

PubMed1988

Nucleotide derivatives of 2,7-diaminomitosene.

Treatment of mitomycin C with pyrimidine nucleotides in acidic media produced derivatives of 2,7-diaminomitosene in which C-1 was covalently bound to the phosphate group of the nucleotides. On reduction, these derivatives liberated the nucleotides and a mitomycin intermediate that alkylated DNA. Their reduction in the presence of 2'-deoxyguanosine produced some bifunctional alkylation as did mitomycin C. They were readily taken up by L1210 leukemia cells, in which they showed potent cytotoxicity. These properties suggest that they are acting as prodrugs capable of conversion into two active species. The uridylate derivative showed activity comparable to that of mitomycin C against P-388 leukemia in mice.

Alkylation↗

PubMed1988

Phase I-II trial of interferon-alpha 2b by continuous subcutaneous infusion over 28 days.

Interferon-alpha 2b (IFN-alpha) was administered by continuous subcutaneous (s.c.) infusion to 23 patients with hematologic malignancies or metastatic solid tumors: 5 patients with multiple myeloma, 3 with malignant melanoma, 2 with chronic myelogenous leukemia (CML), 10 patients with renal cell cancer, and 3 patients with other solid tumors. Drug was delivered by continuous s.c. infusion for 28 days (1 cycle) at daily dose levels of 0.7, 1.4, 2.5, 3.6, or 5.0 X 10(6) IU/m2 to 3, 3, 3, 8, and 6 patients, respectively. At the highest dose level, a severe flu-like syndrome was seen in 3 patients and severe gastrointestinal toxicity in 2 patients. The maximally tolerated dose (MTD) was 3.6 X 10(6) IU/m2.day and the principal toxicity was a mild to moderate flu-like syndrome. Local skin reactions were occasionally noted at all dose levels if the s.c. needle site was not rotated every 3-4 days. At dose levels of 2.5-3.6 X 10(6) IU/m2.day, IFN-alpha serum levels at steady state ranged from 19 to 61 IU/ml. The time to achieve steady-state conditions ranged from 40 to 72 h and at steady state, 24 h area under the concentration time curve (AUC24 h) ranged from 480 to 1,464 IU/ml.h. Objective responses were seen 3 of 17 evaluable patients: 1/7 in renal cell cancer (14%); 1/2 in CML and in one patient with ependymoma. Remissions lasted 4, 8, and 15 months in renal cell, CML, and ependymoma, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1988

New findings in the pharmacokinetic, metabolic, and drug-resistance aspects of mitomycin C.

The pharmacokinetics of mitomycin C are reviewed from reports using specific and sensitive high-performance liquid chromatography (HPLC) assays. These studies demonstrate a rapid, biphasic elimination pattern for the drug: alpha half-life of 8 minutes and beta, or terminal, half-life of 48 minutes. Urinary elimination of intact drug is minimal (8% to 10% of a dose), whereas biliary drug levels may exceed those in the plasma. There was no evidence of dose dependent pharmacokinetics over a wide range of doses and patient populations, including pediatric solid tumor patients. Metabolic studies with mitomycin C have demonstrated an absolute requirement for reductive enzymatic activation of the drug to mono- and bifunctional alkylating species. The preferred DNA target for covalent attachment by mitomycin C was found to be the N2 position of guanine. Chemical metabolites of activated mitomycin C were also demonstrated to include 2, 7 diaminomitosene and its cis- and trans-1-hydroxy or 1-phosphate analogues. Also, there was no evidence for hypoxic cell selectivity for mitomycin C in several human tumor cell lines, although some animal tumors unequivocally display this phenomenon. Finally, there are new observations of the development of the multidrug-resistance phenotype in mitomycin C-treated L-1210 cells in vitro. These cells became collaterally resistant to anthracyclines and vinca alkaloids and expressed the P-glycoprotein in cell membranes. The implications of these findings for mitomycin C use in solid tumors in humans is discussed.

Biotransformation↗

PubMed1987

Mitomycin C resistant L1210 leukemia cells: association with pleiotropic drug resistance.

A mitomycin C-resistant (MMCR) strain of L1210 mouse leukemia was developed by continuous drug exposure in vitro. MMC concentrations were increased in a stepwise fashion beginning at 0.033 microM and ending at 0.34 microM. This produced a 10-fold resistant cell line over the parental line. Resistance simultaneously developed to anthracene and anthracycline DNA intercalators, to vinca alkaloids and epipodophyllotoxins but not to cisplatin, bleomycin, fluorouracil or ionizing X-rays. MMC resistance was reversed using the membrane-active agent verapamil. The level of non-protein sulfhydryls was increased 2-fold in the MMCR cells. Intracellular uptake of unchanged MMC was reduced by 40% in the MMCR cells. Cytogenetic analyses demonstrated no recognizable clonal chromosomal alterations unique to the resistant subline and no evidence of double minutes or homogeneously staining regions in the DNA. Gel renaturation analysis failed to document the presence of an amplified DNA domain. Southern blotting of parental and MMCR DNA using a cDNA probe (CHP1) for the P-glycoprotein gene also failed to demonstrate amplification or rearrangement of P-glycoprotein-related homologous sequences. However, an Mr 180,000 glycoprotein was detected in the plasma membranes from MMCR cells. This protein also specifically reacted with a monoclonal antibody (C219) to the P-glycoprotein of Ling and co-workers [Kartner et al., Nature, Lond. 316, 820 (1985)]. These results suggest a pleiotropic drug resistance pattern in the MMCR cells, associated with membrane glycoprotein alterations, enhanced non-protein sulfhydryl levels, and reduced MMC accumulation. This is a novel observation for a resistant cell line selected with an alkylating agent.

Animals↗

PubMed1987

Cisplatin nephrotoxicity: in vitro studies with precision-cut rabbit renal cortical slices.

Severe nephrotoxic side effects limit the use of cisplatin, a potent anticancer drug. In this study, precision-cut renal cortical slices from rabbits were evaluated as a cisplatin nephrotoxicity model. Cortical slices accumulated approximately 180 ppm (195 ppm Pt = 10(-3) M) of platinum(II) after 18 hr of incubation in medium containing 10(-3) M cisplatin. Dose- and time-dependent toxic responses for clinically relevant concentrations of cisplatin (10(-3)-10(-5) M) were apparent using leakage of intracellular K+, ATP, and lactate dehydrogenase (LDH) to determine cell damage. Histopathologic changes were also produced. Intracellular ATP levels dropped significantly after 6 hr of incubation in 10(-3) M cisplatin, and after 12 hr with 10(-4) M cisplatin. Similarly, intracellular K+ levels decreased significantly by 6 hr of incubation with 10(-3) M cisplatin but remained at control levels for 18 hr in the presence of 10(-4) M cisplatin. Decrements in intracellular LDH levels were not seen until after 12 hr of incubation in 10(-3) M cisplatin. The noncytotoxic isomer transplatin at 10(-3) M was not accumulated by slices; however, intracellular ATP levels were depressed. Of the viability parameters evaluated, intracellular K+ and ATP were found to be optimal indicators. Other active platinum analogs, carboplatin and iproplatin, also caused dose- and time-dependent leakage of intracellular K+ and ATP from renal cortical slices. The ranking of nephrotoxicity of the platinate compounds within this system at concentrations adjusted to approximate equivalent therapeutic activity was similar to that observed in vivo (cisplatin = iproplatin greater than carboplatin greater than transplatin). These results suggest that precision-cut renal cortical slices comprise a viable in vitro model for platinum-induced nephrotoxicity studies.

Adenosine Triphosphate↗

PubMed1987

Topical application of a melanotropic peptide induces systemic follicular melanogenesis.

We determined the relative effectiveness of alpha-MSH and a highly potent melanotropin analogue, [Nle4, D-Phe] - alpha-MSH, in stimulating a shift from pheomelanogenesis to eumelanogenesis within hair bulbs of mice. The analogue proved to be at least a hundred times more effective than the native hormone when injected subcutaneously. The two melanotropins were then incorporated into an ointment base and topically applied to a shaved area of the skin on the back of a yellow strain of mice (C57BL/6JAY). Within 24-48 hours eumelanin production was visible within hair bulb melanocytes in both treated and untreated areas of animals. The presence of melanized organelles (eumelanosomes) within melanocytes was confirmed by electron microscopy. These results document the delivery of a peptide hormone through the skin and into the systemic circulation. This is the first demonstration of the delivery of a peptide hormone by percutaneous absorption and may provide a model for a similar route of delivery of other peptide hormones. The hormone analogue has also been delivered across human skin in vitro. Delivery of a melanotropin by a transdermal route may prove to be clinically useful in the treatment of some integumental hypopigmentary disorders in humans.

Administration, Topical↗

PubMed1987

Reduced thiol content in L1210 cells treated with BSO increases DNA crosslinking by melphalan.

Endogenous thiols such as glutathione (GSH) are known to mediate the activity of bifunctional alkylating agents such as melphalan (L-PAM). GSH levels can be reduced by cell growth in the presence of an analog of gamma glutamyl, alpha-aminobutyrate, L-buthionine (S/R) sulfoximine (L-BSO). L-1210 murine lymphocytic leukemia cells grown in vitro in the presence of 10 microM less than 15% L-BSO possessed 1% of the normal GSH levels. This pretreatment regimen did not significantly alter cell viability but did enhance the cytotoxicity produced by a 15 microM-1hr L-PAM treatment. The increased cell killing correlated with enhanced DNA-DNA crosslinking immediately following L-PAM exposure. No effect of BSO pretreatments on the incomplete removal of crosslinks over 36 hr of observation was seen. These results suggest that GSH levels modulate the initial degree of L-PAM-induced DNA crosslinking, but not the long term repair of these lesions.

Animals↗

PubMed1987

High incidence of local venous reactions to esorubicin.

A retrospective analysis was performed on the medical charts of 160 cancer patients who received esorubicin (ESO or 4'deoxydoxorubicin) in a Phase I clinical trial. The purpose of the review was to characterize the incidence of local venous reactions to this investigational doxorubicin (DOX) analog. The impact of prophylactic pretreatments of post-treatment using antihistamines and glucocorticosteroids was also assessed. There were 58 episodes of local reactions to ESO injections (14.3%). These reactions were characterized by local swelling, itching and erythema. Like DOX-induced venous reactions, ESO complications resolved spontaneously after several hours and did not predispose patients to skin ulceration or subsequent general hypersensitivity reactions. Indeed, ESO reactions were more common with initial treatments at low drug doses of only 10-15 mg/M2 (p less than .05 by Chi-square analysis). One case of ESO extravasation (about 5mg) was successfully managed with topical cooling. The use of antihistamines and corticosteroids was ineffective at preventing local reactions. However, when these drugs were administered after a reaction had ensued, symptoms were lessened significantly in half of the patients treated (p less than .05). The results of this review suggest that ESO causes a four-fold greater incidence of local venous reactions than with the parent DOX.

Adult↗

PubMed1987

Dose-dependent skin ulcers in mice treated with DNA binding antitumor antibiotics.

The DNA-binding agents daunomycin (DAU-NO), mithramycin (MITH), dactinomycin (ACT-D), amsacrine (mAMSA) and esorubicin (ESO) were tested for local vesicant potential in a quantitative intradermal mouse skin model. Only MITH, which adlineates but doses not intercalate DNA, did not produce dose-dependent skin ulcerations in the mouse. The anthracycline antibiotics DAUNO and ESO produced the largest skin ulcers when administered intradermally at clinically relevant doses (adjusted on the basis of comparable body surface areas). Numerous local pharmacologic adjuvants were tested for activity to decrease skin ulceration patterns in mice given one of the DNA intercalators. Inactive local adjuvants included heat, cold, saline, hyaluronidase, glucorticosteroids and isoproternol. Only one adjuvant, topical dimethylsulfoxide (DMSO), was found to reduce DAUNO skin lesions. A single topical DMSO application significantly decreased ulceration size to almost half of control levels. However, it was ineffective for the other intercalating agents. These results show that the DNA intercalators DAUNO, ESO and ACT-D are potent vesicants in a mammalian skin model. These vesicant agents must be administered cautiously to prevent extravasation. No single local adjuvant treatment can be recommended for extravasation of these drugs in the clinic. One significant exception is DAUNO, where topical DMSO may reduce clinical toxicities.

Adjuvants, Pharmaceutic↗