Differential toxicity of camptothecin, topotecan and 9-aminocamptothecin to human, canine, and murine myeloid progenitors (CFU-GM) in vitro

Erickson‐Miller, Connie L.; May, Richard; Tomaszewski, Joseph E.; Osborn, Blaire L.; Murphy, Martin J.; Page, John G.; Parchment, Ralph E.

doi:10.1007/s002800050600

Cited by 101 publications

(65 citation statements)

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“…As an S phase-specific drug whose cytotoxicity operates during DNA synthesis, optimal therapeutic efficacy requires prolonged exposure to 9-AC concentrations exceeding a minimum threshold [14]. Due to greater sensitivity of humans (compared to animals) to its myelosuppressive effects, dose-dependent myelosuppression has precluded the use of the 9-AC levels required to achieve plasma concentrations necessary for optimal antitumor activity [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Gao

Lü

Kopečková

et al. 2007

Journal of Controlled Release

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A water soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer -9-aminocamptothecin (9-AC) conjugate was designed for oral colon-specific drug delivery for the treatment of colon cancer. Comparative studies between the polymer conjugate and free drug have been performed to assess their biodistribution and pharmacokinetics in mice. After oral administration of equal doses of the polymer conjugate or free 9-AC, the drug concentrations in major organs at fixed time points were determined using an HPLC-fluorescence assay. Only 2±1% of 9-AC released from the polymer conjugate was detected in small intestine (SI), and the mean peak concentration of free 9-AC was 45-fold higher than that from released drug. Colon-specific release of 9-AC produced high local concentrations. The mean peak concentration of released 9-AC in cecal contents, feces, cecal tissue, and colon tissue were, respectively, 3.2-fold, 3.5-fold, 2.2-fold and 1.6-fold higher than that using free 9-AC. In plasma, the high and sharp drug concentration profile from free drug was in contrast to the relatively low and flat pharmacokinetic profile obtained from drug released from the HPMA copolymer. There was no significant difference between released and free drug for the area under the concentration-time curve (AUC) and bioavailability values. As a consequence of the colonspecific release of unmodified 9-AC from the polymer conjugate, antitumor efficacy can be anticipated to be enhanced due to prolonged colon tumor exposure to higher and more localized drug concentrations.

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Section: Introductionmentioning

confidence: 99%

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Gao

Lü

Kopečková

et al. 2007

Journal of Controlled Release

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“…Colony counts (normalized as a percentage of control) at each concentration were then plotted to generate the concentrationresponse curve. As previously reported (Erickson-Miller et al, 1997;Parchment et al, 1994Parchment et al, , 1998Pessina et al, 2003), the endpoint of the assay for quantifying inter-species differences in susceptibility to drug toxicity is the IC 90 , which is the concentration that inhibits colony formation by 90%. IC 90 values were calculated from log-linear regression on concentrationresponse between the flanking data points on either side of the 90% inhibition level.…”

Section: In Vitro Comparative Myelotoxicity Assaymentioning

confidence: 99%

“…Dog bone marrow aspirates were collected sterilely from the iliac crest or femoral canal of donor beagle dogs into a 50 ml syringe containing sodium heparin and gentamicin to final concentrations of 10 IU/ml and 20 μg/ml, respectively. CFU-GM assays were performed as previously described (Erickson-Miller et al, 1997;Parchment, 1998;Parchment et al, 1993Parchment et al, , 1994Parchment et al, , 1998, except that species-specific recombinant GM-CSF was used as the sole cytokine in each culture.…”

Section: In Vitro Comparative Myelotoxicity Assaymentioning

confidence: 99%

Integration of in vivo and in vitro approaches to characterize the toxicity of Antalarmin, a corticotropin-releasing hormone receptor antagonist

et al. 2008

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Non-clinical studies were conducted to evaluate the toxicity of Antalarmin, a corticotropin-releasing hormone type 1 receptor antagonist being developed for therapy of stress-related pathologies. Antalarmin was not genotoxic in bacterial mutagenesis assays, mammalian cell mutagenesis assays, or in vivo DNA damage assays. In a 14-day range-finding study in rats, Antalarmin doses ≥ 500 mg/ kg/day (3000 mg/m 2 /day) induced mortality. In a 90-day toxicity study in rats, no gross toxicity was seen at doses of 30, 100, or 300 mg/kg/day (180, 600, or 1800 mg/m 2 /day, respectively). Antalarmin (300 mg/kg/day) induced mild anemia, increases in serum γ-glutamyl transferase activity, and microscopic hepatic pathology (bile duct hyperplasia and epithelial necrosis, periportal inflammation). Microscopic renal changes (cortical necrosis, inflammation, hypertrophy, nephropathy) were observed in rats at all Antalarmin doses. In a 14-day range-finding study in dogs, Antalarmin doses ≥ 50 mg/kg/day (1000 mg/m 2 /day) induced repeated emesis and bone marrow suppression. In a 90-day toxicity study in dogs, Antalarmin (4, 8, or 16 mg/kg/day [80, 160, or 320 mg/m 2 /day, respectively]) induced bone marrow and lymphoid depletion, but no gross toxicity. Comparative in vitro studies using rat, dog, and human neutrophil progenitors demonstrated that canine bone marrow cells are highly sensitive to Antalarmin cytotoxicity, while rat and human bone marrow cells are relatively insensitive. As such, the bone marrow toxicity observed in dogs is considered likely to over-predict Antalarmin toxicity in humans. The hepatic and renal toxicities seen

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“…Differential sensitivity between murine and human myeloid progenitors explains why the curative doses of topoisomerase-I inhibitors in mice with human tumor xenografts are not achievable in patients. 61 21. Gemzar/Gemcitabine.…”

Section: Velcade/bortezomib (Ps-341)mentioning

confidence: 99%

Analysis of FDA Approved Anticancer Drugs Reveals the Future of Cancer Therapy

Blagosklonny¹

2004

Cell Cycle

124

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This review discusses 26 new anticancer drugs approved by the FDA in the past decade. Based on their targets, these anticancer agents can be divided into three groups. The first group contains cancer-selective or semi-selective drugs that are effective in rare kinase-addictive cancers. For other malignancies, semi-selective drugs have to be judiciously combined with nonselective agents. The second group includes analogs of classic cytotoxic agents such as DNA alkylating agents, nucleoside analogs and anti-microtubule agents. As expected, they have a marginal advantage over the existing cytotoxic drugs, nevertheless are more effective (in common cancers) than semi-selective agents. The third is a diverse group of tissue-selective agents that essentially attack the normal tissues of tumor origin and thus exploit the tissue-specific similarities between normal and cancer cells. Our analysis predicts that monotherapy with semi-selective agents will be limited to rare cancers. In most cancers, however, two anticancer strategies may be most fruitful: (a) combinations of cytotoxic drugs with semi-selective agents aimed at matching targets and (b) tissue-selective therapy aimed at normal and tumor cells of the same tissues.

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Differential toxicity of camptothecin, topotecan and 9-aminocamptothecin to human, canine, and murine myeloid progenitors (CFU-GM) in vitro

Cited by 101 publications

References 0 publications

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Integration of in vivo and in vitro approaches to characterize the toxicity of Antalarmin, a corticotropin-releasing hormone receptor antagonist

Analysis of FDA Approved Anticancer Drugs Reveals the Future of Cancer Therapy

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