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Background: Oxaliplatin-induced peripheral neuropathy (OIPN) is prevalent among gastrointestinal cancer survivors and often impairs quality of life (QOL)., Objective: This pilot randomized controlled trial aimed to explore the effect of an 8-week home-based brisk walking (the "MI-Walk") intervention on (1) OIPN severity and (2) QOL at 8 weeks, compared with physical activity (PA) education alone in oxaliplatin-receiving adults with gastrointestinal cancer., Interventions/methods: Participants (N = 57) recruited from 5 infusion sites received PA education at their second oxaliplatin visit, followed by phone assessments of adverse events over 8 weeks. Half (n = 29) received additional MI-Walk intervention motivational supports (eg, a Fitbit Charge 2 and motivational enhancement therapy sessions). Self-reported OIPN, QOL, and PA were measured before and after intervention., Results: The intervention compared with the control condition had no effect on sensory OIPN (mean difference [] = -0.01; P > .99), motor OIPN (=2.39; P = .17), and QOL (= -1.43; P > .99). Eight-week sensory (=11.48 ± 0.38) and motor OIPN severities ( = 7.48 ± 0.36) were mild but higher than baseline (P ≤ .01). Self-reported PA level increased over time in both groups (=44.85; P = .01). Averaging ≥225 moderate to vigorous PA minutes per week led to less sensory OIPN, particularly finger/hand tingling (= -26.35; P = .01)., Conclusions: This study failed to detect beneficial effects of the MI-Walk intervention; however, the findings suggest that aerobic walking may blunt but not completely prevent OIPN. Further research is necessary., Implications for Practice: Although the effectiveness of brisk walking in reducing OIPN is unclear, this study supports prior evidence that moderate to vigorous PA is beneficial and safe during chemotherapy treatment., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Lack of activation in self-care can compromise a patient's ability to monitor and manage cancer treatment-related side effects, such as chemotherapy-induced peripheral neuropathy (CIPN). The web-based Carevive® Care Planning System (CPS) was developed to promote evidence-based symptom assessment and treatment by enhancing patients' involvement in their own care. The purpose of this single-arm, pre-test/post-test, prospective study was to examine whether the CPS can promote patient activation in CIPN symptom assessment and management. Seventy-five women with breast cancer receiving neurotoxic chemotherapy were recruited from a Comprehensive Cancer Center. Using standardized neuropathy measures embedded within the CPS, patients reported their CIPN symptoms over three consecutive clinical visits and completed the Patient Activation Measure (PAM) at the first and third visits. Mean changes in PAM scores between visits were compared using repeated measure analysis of covariance, adjusting for age. At baseline, patients were diagnosed with cancer within the past year (94.7%), highly activated (85% Level III/IV), and had a mean age of 51.3. PAM scores improved significantly from 67.15 (SD = 13.5; range = 47-100) at visit one to 69.29 (SD = 16.18; range = 47-100) (p = 0.02) (n = 62) at visit three. However, patients perceived the CPS to be of minimal value because it solely focused on CIPN and, for many, CIPN was not severe enough to motivate them to seek out symptom management information. Further research is needed to assess the utility of the CPS in promoting activation in the assessment and management of varying cancer treatment-related symptoms.

Purpose: The aim of this study is to examine and compare with the validated, paper/pencil European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy Scale (QLQ-CIPN20), the psychometric properties of three electronically administered patient reported outcome (PRO) measures of chemotherapy-induced peripheral neuropathy (CIPN): (1) the two neuropathy items from the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), (2) the QLQ-CIPN20, and (3) the 0-10 Neuropathy Screening Question (NSQ)., Methods: We employed a descriptive, cross-sectional design and recruited 25 women with breast cancer who were receiving neurotoxic chemotherapy at an academic hospital. Participants completed the paper/pencil QLQ-CIPN20 and electronic versions of the QLQ-CIPN20, PRO-CTCAE, and NSQ. Internal consistency reliability, intraclass correlation, and concurrent and discriminant validity analyses were conducted., Results: The alpha coefficients for the electronic QLQ-CIPN20 sensory and motor subscales were 0.76 and 0.75. Comparison of the electronic and paper/pencil QLQ-CIPN20 subscales supported mode equivalence (intraclass correlation range >0.91). Participants who reported the presence of numbness/tingling via the single-item NSQ reported higher mean QLQ-CIPN20 sensory subscale scores (p < 0.001). PRO-CTCAE neuropathy severity and interference items correlated well with the QLQ-CIPN20 electronic and paper/pencil sensory (r = 0.76; r = 0.70) and motor (r = 0.55; r = 0.62) subscales, and with the NSQ (r = 0.72; r = 0.44)., Conclusion: These data support the validity of the electronically administered PRO-CTCAE neuropathy items, NSQ, and QLQ-CIPN20 for neuropathy screening in clinical practice. The electronic and paper/pencil versions of the QLQ-CIPN can be used interchangeably based on evidence of mode equivalence.

Purpose: Clinical practice guidelines on chemotherapy-induced peripheral neuropathy (CIPN) use the NCI Common Terminology Criteria for Adverse Events (CTCAE), while recent clinical trials employ a potentially superior measure, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN twenty-item scale (QLQ-CIPN20), a patient-reported outcome (PRO). Practitioners and researchers lack guidance, regarding how QLQ-CIPN20 results relate to the traditional CTCAE during the serial assessment of patients undergoing chemotherapy., Methods: Two large CIPN clinical trial datasets (538 patients) pairing QLQ-CIPN20 and CTCAE outcomes were analyzed using a multivariable linear mixed model with QLQ-CIPN20 score as the outcome variable, CTCAE grade as the main effect, and patient as random effect (accounting for internal correlation of serial measures)., Results: The association between QLQ-CIPN20 scores and CTCAE grades was strong (p < 0.0001), whereby patients with higher CTCAE grade had worse QLQ-CIPN20 scores. Some variation of QLQ-CIPN20 scores was observed based on drug, treatment, and cycle. While there was a marked difference in the mean QLQ-CIPN20 scores between CTCAE grades, the ranges of QLQ-CIPN20 scores within each CTCAE grade were large, leading to large overlap in CIPN20 scores across CTCAE grades., Conclusions: A strong positive association of QLQ-CIPN20 scores and CTCAE grade provides evidence of convergent validity as well as practical guidance, as to how to quantitatively interpret QLQ-CIPN20 scores at the study level in terms of the traditional CTCAE. The present results also highlight an important clinical caveat, specifically, that conversion of a specific QLQ-CIPN20 score to a specific CTCAE score may not be reliable at the level of an individual patient.

Purpose/objectives: To test the content validity of a 16-item version of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy (QLQ-CIPN20). 
., Research Approach: Cross-sectional, prospective, qualitative design. 
., Setting: Six outpatient oncology clinics within the University of Michigan Health System's comprehensive cancer center in Ann Arbor. 
., Participants: 25 adults with multiple myeloma or breast, gynecologic, gastrointestinal, or head and neck malignancies experiencing peripheral neuropathy caused by neurotoxic chemotherapy. 
., Methodologic Approach: Cognitive interviewing methodology was used to evaluate the content validity of a 16-item version of the QLQ-CIPN20 instrument.
., Findings: Minor changes were made to three questions to enhance readability. Twelve questions were revised to define unfamiliar terminology, clarify the location of neuropathy, and emphasize important aspects. One question was deleted because of clinical and conceptual redundancy with other items, as well as concerns regarding generalizability and social desirability. 
., Interpretation: Cognitive interviewing methodology revealed inconsistencies between patients' understanding and researchers' intent, along with points that required clarification to avoid misunderstanding. 
., Implications for Nursing: Patients' interpretations of the instrument's items were inconsistent with the intended meanings of the questions. One item was dropped and others were revised, resulting in greater consistency in how patients, clinicians, and researchers interpreted the items' meanings and improving the instrument's content validity. Following additional revision and psychometric testing, the QLQ-CIPN20 could evolve into a gold-standard CIPN patient-reported outcome measure.

Duloxetine is an effective treatment for oxaliplatin-induced painful chemotherapy-induced peripheral neuropathy (CIPN). However, predictors of duloxetine response have not been adequately explored. The objective of this secondary and exploratory analysis was to identify predictors of duloxetine response in patients with painful oxaliplatin-induced CIPN. Patients (N = 106) with oxaliplatin-induced painful CIPN were randomised to receive duloxetine or placebo. Eligible patients had chronic CIPN pain and an average neuropathic pain score ≥4/10. Duloxetine/placebo dose was 30 mg/day for 7 days, then 60 mg/day for 4 weeks. The Brief Pain Inventory-Short Form and the EORTC QLQ-C30 were used to assess pain and quality of life, respectively. Univariate and multiple logistic regression analyses were performed to identify demographic, physiologic and psychological predictors of duloxetine response. Higher baseline emotional functioning predicted duloxetine response (≥30% reduction in pain; OR 4.036; 95% CI 0.999-16.308; p = 0.050). Based on the results from a multiple logistic regression using patient data from both the duloxetine and placebo treatment arms, duloxetine-treated patients with high emotional functioning are more likely to experience pain reduction (p = 0.026). In patients with painful, oxaliplatin-induced CIPN, emotional functioning may also predict duloxetine response. ClinicalTrials.gov, Identifier NCT00489411., (© 2015 John Wiley & Sons Ltd.)

Cancer treatment-related chronic neuropathic pain (NP) is a pervasive and distressing problem that negatively influences function and quality of life for countless cancer survivors. It occurs because of cancer treatment-induced damage to peripheral and central nervous system structures. NP becomes chronic when pain signal transmission persists, eventually sensitizing neurons in the dorsal horn and other pain-processing regions in the central nervous system. Frequently overlooked, NP due to cancer treatment has been understudied. Consequently, only a few pharmacologic interventions have been shown to be effective based on the results of randomized controlled trials. Future research designed to explore pathophysiologic mechanisms and effective mechanism-targeted interventions is sorely needed.

Purpose/objectives: To explore nurses' practice patterns, knowledge, and barriers related to chemotherapy-induced peripheral neuropathy (CIPN)., Design: Descriptive, cross-sectional., Setting: The United States., Sample: 408 oncology nurses., Methods: A team of eight experts met and developed the CIPN nurse knowledge and preferences survey, which was electronically sent to randomly selected nurses., Main Research Variables: The survey assessed nurses' knowledge and practice patterns regarding assessment strategies and barriers, evidence-based interventions, preferences for education, and perceived gaps in scientific knowledge., Findings: Nurses in the survey lacked knowledge regarding neurotoxicity of specific agents and evidence-based treatments. CIPN-focused physical examinations and standardized measurement tools were infrequently used during assessment. The most frequently reported barriers to CIPN assessment included lack of access to measurement tools, lack of specialized skills needed for assessment, lack of confidence, and lack of time. Recommendations for future research included CIPN prevention research, exploration of CIPN-related effects on quality of life, and alternative treatments of CIPN. The majority of participants preferred online educational opportunities., Conclusions: Nurses do not consistently integrate evaluation and management of CIPN in their practices., Implications for Nursing: Educational offerings should incorporate web-based CIPN assessment and management content.

Purpose: To provide evidence-based guidance on the optimum prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathies (CIPN) in adult cancer survivors., Methods: A systematic literature search identified relevant, randomized controlled trials (RCTs) for the treatment of CIPN. Primary outcomes included incidence and severity of neuropathy as measured by neurophysiologic changes, patient-reported outcomes, and quality of life., Results: A total of 48 RCTs met eligibility criteria and comprise the evidentiary basis for the recommendations. Trials tended to be small and heterogeneous, many with insufficient sample sizes to detect clinically important differences in outcomes. Primary outcomes varied across the trials, and in most cases, studies were not directly comparable because of different outcomes, measurements, and instruments used at different time points. The strength of the recommendations is based on the quality, amount, and consistency of the evidence and the balance between benefits and harms., Recommendations: On the basis of the paucity of high-quality, consistent evidence, there are no agents recommended for the prevention of CIPN. With regard to the treatment of existing CIPN, the best available data support a moderate recommendation for treatment with duloxetine. Although the CIPN trials are inconclusive regarding tricyclic antidepressants (such as nortriptyline), gabapentin, and a compounded topical gel containing baclofen, amitriptyline HCL, and ketamine, these agents may be offered on the basis of data supporting their utility in other neuropathic pain conditions given the limited other CIPN treatment options. Further research on these agents is warranted., (© 2014 by American Society of Clinical Oncology.)

Purpose: This clinimetric analysis was conducted to evaluate the reliability, validity, and responsiveness to changeover time of the QLQ-CIPN20 when used to quantify patient-reported chemotherapy-induced peripheral neuropathy (CIPN)., Methods: Participants recruited to four cooperative group trials were pooled to create two groups (n = 376, 575): those who did versus did not receive neurotoxic chemotherapy. QLQ-CIPN20 internal consistency reliability was assessed using Cronbach's alpha coefficients. Instrument validity was assessed using factor analysis, by evaluating score correlations with other CIPN and pain measures, and by comparing scores between contrasting groups. Cohen's d was used to assess responsiveness to change., Results: Alpha coefficients for the sensory, motor, and autonomic scales were 0.88, 0.88, and 0.78, respectively. However, autonomic scale and hearing loss items exhibited low item-item correlations (r ≤ 0.30) and thus were deleted. Moderate correlations were found between QLQ-CIPN20 and Brief Pain Inventory pain severity items (r 0.30-0.57, p ≤ .0001). Correlation between the QLQ-CIPN20 sensory and toxicity grading scale scores was low (r = .20; p ≤ .01). Mean scores were higher (worse) (p ≤ 0.0001) in individuals who did versus did not receive neurotoxic chemotherapy. The sensory and motor scales exhibited moderate-high responsiveness to change (Cohen's d = 0.82 and 0.48, respectively). Factor analysis indicated that the 16-item version formed distinct factors for lower and upper extremity CIPN, delineating typical distal to proximal CIPN progression., Conclusions: Results provide support for QLQ-CIPN20 sensory and motor scale reliability and validity. The more parsimonious and clinically relevant 16-item version merits further consideration.

Importance: There are no known effective treatments for painful chemotherapy-induced peripheral neuropathy., Objective: To determine the effect of duloxetine, 60 mg daily, on average pain severity., Design, Setting, and Patients: Randomized, double-blind, placebo-controlled crossover trial at 8 National Cancer Institute (NCI)-funded cooperative research networks that enrolled 231 patients who were 25 years or older being treated at community and academic settings between April 2008 and March 2011. Study follow-up was completed July 2012. Stratified by chemotherapeutic drug and comorbid pain risk, patients were randomized to receive either duloxetine followed by placebo or placebo followed by duloxetine. Eligibility required that patients have grade 1 or higher sensory neuropathy according to the NCI Common Terminology Criteria for Adverse Events and at least 4 on a scale of 0 to 10, representing average chemotherapy-induced pain, after paclitaxel, other taxane, or oxaliplatin treatment., Interventions: The initial treatment consisted of taking 1 capsule daily of either 30 mg of duloxetine or placebo for the first week and 2 capsules of either 30 mg of duloxetine or placebo daily for 4 additional weeks., Main Outcome Measures: The primary hypothesis was that duloxetine would be more effective than placebo in decreasing chemotherapy-induced peripheral neuropathic pain. Pain severity was assessed using the Brief Pain Inventory-Short Form "average pain" item with 0 representing no pain and 10 representing as bad as can be imagined., Results: Individuals receiving duloxetine as their initial 5-week treatment reported a mean decrease in average pain of 1.06 (95% CI, 0.72-1.40) vs 0.34 (95% CI, 0.01-0.66) among those who received placebo (P = .003; effect size, 0.513). The observed mean difference in the average pain score between duloxetine and placebo was 0.73 (95% CI, 0.26-1.20). Fifty-nine percent of those initially receiving duloxetine vs 38% of those initially receiving placebo reported decreased pain of any amount., Conclusion and Relevance: Among patients with painful chemotherapy-induced peripheral neuropathy, the use of duloxetine compared with placebo for 5 weeks resulted in a greater reduction in pain., Trial Registration: clinicaltrials.gov Identifier: NCT00489411.

To aid preclinical development of novel therapeutics for myeloma, an in vivo model which recapitulates the human condition is required. An important feature of such a model is the interaction of myeloma cells with the bone marrow microenvironment, as this interaction modulates tumour activity and protects against drug-induced apoptosis. Therefore NOD/SCIDγc(null) mice were injected intra-tibially with luciferase-tagged myeloma cells. Disease progression was monitored by weekly bioluminescent imaging (BLI) and measurement of paraprotein levels. Results were compared with magnetic resonance imaging (MRI) and histology. Assessment of model suitability for preclinical drug testing was investigated using bortezomib, melphalan and two novel agents. Cells engrafted at week 3, with a significant increase in BLI radiance occurring between weeks 5 and 7. This was accompanied by an increase in paraprotein secretion, MRI-derived tumour volume and CD138 positive cells within the bone marrow. Treatment with known anti-myeloma agents or novel agents significantly attenuated the increase in all disease markers. In addition, intra-tibial implantation of primary patient plasma cells resulted in development of myeloma within bone marrow. In conclusion, using both myeloma cell lines and primary patient cells, we have developed a model which recapitulates human myeloma by ensuring the key interaction of tumour cells with the microenvironment.

Background: Assessment of chemotherapy-induced peripheral neuropathy signs and symptoms has been hampered because of the lack of simple, reliable, and valid measures., Objective: The study objective was to examine the internal consistency and interrater reliability as well as the structural validity of a 5-component total neuropathy score-reduced (TNSr) variant and a chemotherapy-induced neuropathy-specific Neuropathic Pain Scale., Methods: One hundred seventeen outpatients receiving taxanes or platinums were assessed by a consistent nurse practitioner using the 2 instruments. Ten subjects participated in interrater reliability testing., Results: Mean scores and SDs for individual items were low. The strength item was deleted because of low interitem correlations and a floor effect. The reflex item was deleted because of low interitem correlations and its negative influence on Cronbach alpha. Pin sensibility was deleted because of low factor loadings. The TNSr-short form and the chemotherapy-induced neuropathy-specific Neuropathic Pain Scale formed 2 distinct factors, providing evidence of structural validity. Cronbach alpha's for the 2 instruments were .80 and .96, respectively. The TNSr interrater reliability results suggested acceptable rater concordance, but minor revisions could further improve scoring precision., Conclusion: Clinimetric evidence supports the use of 2 new instruments when monitoring taxane- and platinum-related neuropathy and pain. Further instrument modifications are recommended, followed by additional testing in diverse populations., Implications for Practice: With these new instruments, nurses can more easily incorporate prospective neuropathy assessment into daily clinical practice. The outcome will be improved symptom awareness by oncology clinicians and patients, leading to fewer chemotherapy-induced peripheral neuropathy-related devastating effects on functionality and quality of life.

The dinitrobenzamide mustards are a class of bioreductive nitro-aromatic anticancer prodrugs, of which a phosphorylated analog (PR-104) is currently in clinical development. They are bioactivated by tumor reductases to form DNA cross-linking cytotoxins. However, their biotransformation in normal tissues has not been examined. Here we report the aerobic in vitro metabolism of three N-(2 hydroxyethyl)-3,5-dinitrobenzamide 2-mustards and the corresponding nonmustard analog in human, mouse, rat, and dog hepatic S9 preparations. These compounds have a range of mustard structures (-N(CH(2)CH(2)X)(2) where X = H, Cl, Br, or OSO(2)Me). Four metabolic routes were identified: reduction of either nitro group, N-dealkylation of the mustard, plus O-acetylation, and O-glucuronidation of the hydroxyethyl side chain. Reduction of the nitro group ortho to the mustard resulted in intramolecular alkylation and is considered to be an inactivation pathway, whereas reduction of the nitro group para to the mustard generated potential DNA cross-linking cytotoxins. N-Dealkylation inactivated the mustard moiety but may result in the formation of toxic acetaldehyde derivatives. Increasing the size of the nitrogen mustard leaving group abrogated the ortho-nitroreduction and N-dealkylation routes and thereby improved overall metabolic stability but had little effect on aerobic para-nitroreduction. All four compounds underwent O-glucuronidation of the hydroxyethyl side chain and further studies to elucidate the relative importance of this pathway in vivo are in progress.

Purpose/objectives: To describe the psychometric properties, clinical significance, and utility of the Total Neuropathy Score (TNS), a composite measurement tool used to assess chemotherapy-induced peripheral neuropathy (CIPN)., Data Sources: Published articles and abstracts and pertinent article references., Data Synthesis: CIPN has been quantified inadequately because of the lack of an optimal measurement tool. The TNS is the most comprehensive composite tool to have been tested in oncology settings. The tool assesses neuropathy signs and symptoms and incorporates nerve conduction study results but inadequately assesses neuropathy-related pain severity. Seven studies have reported on the TNS's psychometric properties., Conclusions: Initial but limited evidence supports the TNS's psychometric properties. The tool is too burdensome and inadequately assesses pain severity. Further revision and testing of the tool are recommended., Implications for Nursing: TNS simplification and further psychometric testing could lead to future use by oncology nurses.

New blood vessel formation is essential for tumor growth and metastatic spread. Integrins alpha(v)beta3 and alpha(v)beta5 are arginine-glycine-aspartic acid-dependent adhesion receptors that play a critical role in angiogenesis. Hence, selective dual alpha(v)beta3 and alpha(v)beta5 antagonists may represent a novel class of angiogenesis and tumor-growth inhibitors. Here, an arginine-glycine-aspartic acid-based peptidomimetic library was screened to identify alpha(v)beta3 antagonists. Selected compounds were then modified to generate potent and selective dual inhibitors of alpha(v)beta3 and alpha(v)beta5 receptors. One of these compounds, SCH 221153, inhibited the binding of echistatin to alpha(v)beta3 (IC50 = 3.2 nM) and alpha(v)beta5 (IC50 = 1.7 nM) with similar potency. Its IC50 values for related alpha(IIb)beta3 and alpha5beta1 receptors were 1294 nM and 421 nM, respectively, indicating that SCH 221153 is highly selective for alpha(v)beta3 and alpha(v)beta5 receptors. In cell-based assays, SCH 221153 inhibited the binding of echistatin to alpha(v)beta3- and alpha(v)beta5-expressing 293 cells and blocked the adhesion of endothelial cells to immobilized vitronectin and fibroblast growth factor 2 (FGF2). SCH 221153, but not the inactive analogue SCH 216687, was effective in inhibiting FGF2 and vascular endothelial growth factor-induced endothelial cell proliferation in vitro with an IC50 equal to 3-10 microM. Angiogenesis induced by FGF2 in the chick chorioallantoic membrane assay was also inhibited by SCH 221153. Finally, SCH 221153 exerted a significant inhibition on tumor growth induced by intradermal or s.c. injection of human melanoma LOX cells in severe combined immunodeficient mice.

Flavopiridol is a novel semisynthetic flavone derivative of the alkaloid rohitukine. Flavopiridol is known to inhibit potently the activity of multiple cyclin-dependent kinases. We have assessed its effects on normal and malignant cells in preclinical animal models of localized and disseminated human hematopoietic neoplasms. Flavopiridol, when administered as daily bolus intravenous (IV) injections, produced selective apoptosis of cells in the thymus, spleen, and lymph nodes, resulting in atrophy of these organs. With the exception of the intestinal crypts, apoptosis or tissue damage was absent in all other organs investigated (kidneys, liver, lungs, bone/bone marrow, muscle, and heart). Flavopiridol had a marked apoptotic effect documented by DNA nick-end labeling, or DNA agarose gels in xenografts of human hematopoietic tumors HL-60, SUDHL-4, and Nalm/6. After treatment with 7.5 mg/kg flavopiridol bolus IV or intraperitoneal on each of 5 consecutive days, 11 out of 12 advanced stage subcutaneous (s.c.) human HL-60 xenografts underwent complete regressions, and animals remained disease-free several months after one course of flavopiridol treatment. SUDHL-4 s.c. lymphomas treated with flavopiridol at 7.5 mg/kg bolus IV for 5 days underwent either major (two out of eight mice) or complete (four out of eight mice) regression, with two animals remaining disease-free for more than 60 days. The overall growth delay was 73.2%. The acquired immunodeficiency syndrome-associated lymphoma AS283 showed no significant response when flavopiridol was used in advanced s.c. tumors, but when treatment was initiated in early stages, there was a complete regression of the early tumors, and a significant overall growth delay (>84%). When flavopiridol was used in severe combined immunodeficient mice bearing disseminated human acute lymphoblastic leukemia Nalm/6 cells, there was 15-day prolongation in survival (P = .0089). We conclude that flavopiridol greatly influences apoptosis in both normal and malignant hematopoietic tissues. This activity was manifested in our study as a potent antileukemia or antilymphoma effect in human tumor xenografts, which was dose and schedule dependent. These findings provide compelling evidence for the use of flavopiridol in human hematologic malignancies.

Some ellipticine derivative salts, including 9-chloro-2-methylellipticinium (CME), have been found to have a marked selectivity against all eight brain tumor cell lines of the U.S. National Cancer Institute's disease-oriented in vitro screen. We initiated in vivo antitumor studies to explore the feasibility for further development of this class of compounds. We found that CME was extremely toxic to nude mice when given i.p. at a dose of 25 mg/kg for 3 consecutive days. Animals treated by this route experienced an increase in hepatic transaminases and histopathological changes in the liver, compatible with mitochondrial damage. In contrast, when the portal circulation was bypassed and the same dose of CME was given i.v., animals tolerated daily bolus injections for 5 consecutive days. This 5-day i.v. bolus schedule had consistent antitumor activity, with 28.1% growth delay on s.c. implanted human U251 gliomas. When the potentially high peaks of CME in the portal circulation were avoided by using a 3-day continuous infusion with osmotic minipumps implanted i.p. to release 3.4 mg kg(-1) h(-1) or 6.6 mg kg(-1) h(-1) CME, there were only modest increases in liver enzymes and leukopenia, but no meaningful antitumor activity was observed. In contrast, continuous infusion in the s.c. space was well tolerated and was accompanied by a demonstrable growth delay in s.c. U251 human gliomas of 37.8%. When CME was used in conjunction with carmustine, etoposide or cisplatin, no synergistic activities were observed, but additive effects were demonstrated. Our pharmacokinetic and disposition studies with CME argue against the notion that large and invasive tumors in the brain lack blood-brain barrier features. When CME was used in animals bearing orthotopically implanted U251 gliomas in the brain of nude mice, the survival of the treated animals was not better than vehicle controls, and the addition of CME to carmustine therapy did not improve the survival of those animals treated with carmustine alone. We conclude that, in spite of its marked cytotoxicity in vitro on a variety of human brain tumor cell lines, including U251 glioma cells, CME has a modest antitumor effect on extracranially implanted U251 glioma tumors, and no beneficial effect in animals bearing the same U251 tumor in the brain, owing to a poor penetration into the brain parenchyma.