Tumor Models and the Discovery and Secondary Evaluation of Solid Tumor Active Agents

Corbett, Thomas H.; Valeriote, Fred; LoRusso, Patricia; Polin, Lisa; Panchapor, Chiab; Pugh, Susan; White, Kathryn; Knight, Jennifer; Demchik, Lisa; Jones, Julie L.; Jones, Lynne A.; Lowichik, Nancy; Biernat, Laura; Foster, Brenda J.; Wozniak, A.; Lisow, Loretta; Valdivieso, Manuel; Baker, Larry; Leopold, Wilbur R.; Sebolt, Judith; Bissery, Marie Christine; Mattes, Ken C.; Dzubow, Janet; Rake, James B.; Perni, Robert B.; Wentland, Mark P.; Coughlin, Susan A.; Shaw, Jyoti; Liversidge, Gary G.; Liversidge, Elaine; Bruno, Joseph G.; Sarpotdar, Pramod P.; Moore, Richard E.; Patterson, Gregory M. L.

doi:10.3109/13880209509067092

Cited by 35 publications

(23 citation statements)

References 11 publications

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“…Murine tumours derived from long-term cell culture passage are frequently less invasive, far less metastatic and less aggressive than the same tumour maintained by animal passage only (Corbett et al, 1987). The drug sensitivities for long-term passaged tumours in vitro can, and do, change frequently (Corbett et al, 1995;Valeriote et al, 1996). In contrast, the sensitivity pattern for a tumour passaged in vivo to a given set of agents remains relatively stable for many years and dozens of transplant generations.…”

Section: Discussionmentioning

confidence: 99%

Variation in RNA expression and genomic DNA content acquired during cell culture

et al. 2004

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Specific chromosomal abnormalities are increasingly recognised to be associated with particular tumour subtypes. These cytogenetic abnormalities define the sites of specific genes, the alteration of which is implicated in the neoplastic process. We used comparative genomic hybridisation (CGH) to examine DNA from different breast and ovarian cancer cell lines for variations in DNA sequence copy number compared with the same normal control. We also compared different sources of the MCF7 breast line by both CGH and cDNA expression arrays. Some of the differences between the subcultures were extensive and involved large regions of the chromosome. Differences between the four subcultures were observed for gains of 2q, 5p, 5q, 6q, 7p, 7q, 9q, 10p, 11q, 13q, 14q, 16q, 18p and 20p, and losses of 4q, 5p, 5q, 6q, 7q, 8p, 11p, 11q, 12q, 13q, 15q, 19p, 19q, 20p, 21q, 22q and Xp. However, few variations were found between two subcultures examined, 5 months apart, from the same initial source. The RNA arrays also demonstrated considerable variation between the three different subcultures, with only 43% of genes expressed at the same levels in all three. Moreover, the patterns of the expressed genes did not always reflect our observed CGH aberrations. These results demonstrate extensive genomic instability and variation in RNA expression during subculture and provide supportive data for evidence that cell lines do evolve in culture, thereby weakening the direct relevance of such cultures as models of human cancer. This work also reinforces the concern that comparisons of published analyses of cultures of the same name may be dangerous.

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Section: Discussionmentioning

confidence: 99%

Variation in RNA expression and genomic DNA content acquired during cell culture

et al. 2004

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“…The methods of protocol design, drug treatment, toxicity evaluation, data analysis, quantification of tumor cell kill, tumor model systems, and the biological significance of the drug treatment results with transplantable tumors have been presented previously [3,7,[14][15][16][17][18][19][20][21][22][23]. A brief description of the methods as they apply to this work is as follows.…”

Section: Methodsmentioning

confidence: 99%

Cryptophycins-309, 249 and other cryptophycin analogs: Preclinical efficacy studies with mouse and human tumors

et al. 2005

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Cryptophycins-1 and 52 (epoxides) were discovered to have in-vitro and in-vivo antitumor activity in the early 1990s. The chlorohydrins of these, Cryptophycins-8 and 55 (also discovered in the early 1990s) were markedly more active, but could not be formulated as stable solutions. With no method to adequately stabilize the chlorohydrins at the time, Cryptophycin-52 (LY 355073) entered clinical trials, producing only marginal antitumor activity. Since that time, glycinate esters of the hydroxyl group of the chlorohydrins have been synthesized and found to provide stability. Three of the most active were compared herein. Cryptophycin-309 (C-309) is a glycinate ester of the chlorohydrin Cryptophycin-296. The glycinate derivative provided both chemical stability and improved aqueous solubility. After the examination of 81 different Cryptophycin analogs in tumor bearing animals, C-309 has emerged as superior to all others. The following %T/C and Log Kill (LK) values were obtained from a single course of IV treatment (Q2d x 5) against early staged SC transplantable tumors of mouse and human origin: Mam 17/Adr [a pgp (+) MDR tumor]: 0%T/C, 3.2 LK; Mam 16/C/Adr [a pgp (-) MDR tumor]: 0%T/C, 3.3 LK; Mam 16/C: 0%T/C, 3.8 LK; Colon 26: 0%T/C, 2.2 LK; Colon 51: 0%T/C, 2.4 LK; Pancreatic Ductal Adenocarcinoma 02 (Panc 02): 0%T/C, 2.4 LK; Human Colon HCT15 [a pgp (+) MDR tumor]: 0%T/C, 3.3 LK; Human Colon HCT116: 0%T/C, 4.1 LK. One additional analog, Cryptophycin-249 (C-249, the glycinate of Cryptophycin-8), also emerged with efficacy rivaling or superior to C-309. However, there was sufficient material for only a single C-249 trial in which a 4.0 LK was obtained against the multidrug resistant breast adenocarcinoma Mam-16/C/Adr. C-309 and C-249 are being considered as second-generation clinical candidates.

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“…The tumor cell kill was calculated as follows: For leukemic survival trials, the log 10 cell kill is calculated from as Log 10 cell kill total (gross) ϭ T Ϫ C/3.32 (Td), where T is the median day of death for the treated group and C is the median day of death for the control group. [37][38][39] The Td (tumor doubling time) is determined from differences in the median days of death of the titered control groups.…”

Section: -Cl-ahpc In Vivo Therapymentioning

confidence: 99%

Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog

Zhang

Dawson²,

Ning³

et al. 2003

Blood

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IntroductionAcute myelogenous leukemia (AML) is a heterogeneous disease composed of numerous subclassifications displaying a wide spectrum of phenotypes. 1,2 The major therapeutic approach to this disease has been the use of chemotherapeutic agents with associated life-threatening toxicity. Although nonspecific in their effects, these regimens have significantly increased the survival of AML patients. [3][4][5] Recently, more targeted therapy has been developed. Treatment of acute promyelocytic leukemia (APL) patients with trans-retinoic acid (tRA) results in the differentiation of the leukemic cells, with 90% of the patients achieving a complete remission. [6][7][8] The tRA exerts its effect by modulating gene expression through its role as a ligand to the retinoic acid nuclear receptors, RARs, with the subsequent binding of this complex to the retinoic acid response element (RARE) consensus sequences located in the regulatory regions of retinoid-responsive genes. 9 The selective sensitivity of APL cells to tRA-mediated differentiation resides in their specific expression of a unique promyelocytic leukemia (PML)-RAR␣ fusion product that results in the subsequent maturation arrest of these cells at the promyelocyte stage [10][11][12] ; exposure of these cells to a micromolar concentration of tRA allows for the degradation of the PML-RAR␣ fusion product, with subsequent maturation of the APL cells. [13][14] Unfortunately, the other AML subtypes as classified by the French-American-British (FAB) classification demonstrate inherent resistance to tRA-mediated differentiation and induction of apoptosis. 15,16 We and others have recently described a novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN/CD437), which is a potent inducer of apoptosis in a variety of cell types and which displays resistance to tRA-mediated differentiation and apoptosis. [17][18][19][20][21] The mechanistic pathways by which AHPN induces apoptosis in malignant cells are not clearly defined. AHPN binds and transactivates both the RAR␤ and RAR␥ receptors. 22,23 The roles of these retinoid nuclear receptors in AHPN-mediated apoptosis are controversial. While some studies have suggested that binding and transactivation of RAR␥ are essential for AHPN/CD437-mediated apoptosis, 24,25 others have indicated that neither the RARs nor the retinoid X receptors (RXRs) to which AHPN does not bind or transactivate are involved. 20,21,26 bloodjournal.org FromIn the present study, we assessed the ability of the AHPN analog 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC/MM002) to induce apoptosis in a number of human AML cell lines as well as in primary cultures of leukemic blasts obtained from patients. The 3-Cl-AHPC differs from AHPN in its inability to recruit RAR coactivators and transactivate the RARs (Zhang et al 27 and data not shown). We found that 3-Cl-AHPC is a potent inducer of apoptosis in these cells, which display resistance to the antiproliferative/differentiating effects of tRA. The 3-C...

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Tumor Models and the Discovery and Secondary Evaluation of Solid Tumor Active Agents

Cited by 35 publications

References 11 publications

Variation in RNA expression and genomic DNA content acquired during cell culture

Variation in RNA expression and genomic DNA content acquired during cell culture

Cryptophycins-309, 249 and other cryptophycin analogs: Preclinical efficacy studies with mouse and human tumors

Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog

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