Discovery of Solid Tumor Active Agents Using a Soft-Agar-Colony-Formation Disk-Diffusion-Assay

Corbett, Thomas H.; Valeriote, Frederick A.; Polin, Lisa; Panchapor, Chiab; Pugh, Susan; White, Kathryn; Lowichik, Nancy; Knight, Jennifer; Bissery, Marie-Christine; Wozniak, A.; LoRusso, Patricia; Biernat, Laura; Polin, Daniel A.; Knight, Lentawn; Biggar, Sandra; Looney, Darrell; Demchik, Lisa; Jones, Julie L.; Jones, Lynne A.; Blair, Scott; Palmer, Kerry; Essenmacher, Sandra; Lisow, Loretta; Mattes, Ken C.; Cavanaugh, Paul F.; Rake, James B.; Baker, Laurence H.

doi:10.1007/978-1-4615-3492-1_3

Cited by 46 publications

(58 citation statements)

References 6 publications

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“…The WSU-DLCL2 is considered a chemotherapyresistant model since it was established from a patient with aggressive lymphoma refractory to therapy (11). Activity score in xenograft models of (+++) or (++++) corresponds with clinical partial and complete response, respectively (16). For rituximab, four of the seven animals survived to the end of the experiment and were tumor free.…”

Section: Resultsmentioning

confidence: 99%

“…The experiment was designed to terminate 150 d from transplantation of tumors (WSU-DLCL2) or injection of cells (WSU-FSCCL) because tumor-free animals at that point are considered disease free and "cured". This duration of experiment exceeds most standard protocols where experiments are usually terminated 90 to 120 d after tumor cell injections (16). Some animals in this study were euthanized after 155 d from transplantation of tumor fragments.…”

Section: Animal Monitoringmentioning

confidence: 97%

“…For the WSU-DLCL2-SCID model, tumor growth inhibition, tumor growth delay, and log 10 kill were used, which are standard measures of tumor response evaluation in subcutaneous xenograft models (16). For the WSU-FSCCL-SCID systemic model, median day of death for each group and number of animals alive at the end of the experiment were used as end points.…”

Section: Determination Of Responsementioning

confidence: 99%

“…For the WSU-FSCCL-SCID systemic model, median day of death for each group and number of animals alive at the end of the experiment were used as end points. This method is applicable to systemic diseases, such as leukemia, that disseminate in internal organs of animals but do not have measurable subcutaneous tumors (16).…”

Section: Determination Of Responsementioning

confidence: 99%

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Superior Antitumor Activity of SAR3419 to Rituximab in Xenograft Models for Non-Hodgkin's Lymphoma

Al‐Katib

Aboukameel

Mohammad³

et al. 2009

Clinical Cancer Research

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Purpose: To investigate the activity of SAR3419, a novel humanized anti-CD19 antibody (huB4), conjugated to a cytotoxic maytansine derivative N 2 '-deacetyl-N 2 '-(4-mercapto-4-methyl-1-oxopentyl) maytansine, in preclinical xenograft models for non-Hodgkin's lymphoma. Experimental Design: Antitumor activity of SAR3419 was assessed as a single agent and in comparison with conventional therapies using a subcutaneous model for diffuse large B-cell lymphoma (WSU-DLCL2) and a systemic model for follicular small cleaved cell lymphoma (WSU-FSCCL) in mice with severe combined immune deficiency. Results: Our results showed that in these chemotherapy-resistant models, SAR3419 was more effective than CHOP (cyclophosphamide-Adriamycin-vincristine-prednisone) regimen or rituximab. Only treatment with SAR3419 led to survival of the whole group of animals to the end of the experiment (150-155 days) in both models. Higher doses of SAR3419 (15 and 30 mg/kg) were more effective than lower dose of 7.5 mg/kg. The immunoconjugation was necessary because neither huB4 nor DM4 alone had significant activity. Treatment with rituximab resulted in antitumor activity in both models comparable with the low dose of SAR3419. Cyclophosphamide-Adriamycin-vincristineprednisone alone showed modest activity in both models. Necropsy and tissue staining in the WSU-FSCCL systemic model revealed that all deaths featured leptomeningeal lymphoma in the control and treated groups. Interestingly, some of the animals that survived to the end of the experiment and seemed healthy at time of euthanasia did show microscopic evidence of lymphoma. Conclusions: Overall, SAR3419 is a very active immunotoxin in preclinical models for human B-cell lymphoma and holds promise as a novel and well-tolerated therapy in B-cell non-Hodgkin's lymphoma.

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Section: Resultsmentioning

confidence: 99%

Section: Animal Monitoringmentioning

confidence: 97%

Section: Determination Of Responsementioning

confidence: 99%

Section: Determination Of Responsementioning

confidence: 99%

See 2 more Smart Citations

Superior Antitumor Activity of SAR3419 to Rituximab in Xenograft Models for Non-Hodgkin's Lymphoma

Al‐Katib

Aboukameel

Mohammad³

et al. 2009

Clinical Cancer Research

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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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A phase 2 study of tasisulam sodium (LY573636 sodium) as second‐line treatment for patients with unresectable or metastatic melanoma

Kirkwood

González

Reintgen

et al. 2011

Cancer

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BACKGROUND: Tasisulam sodium (hereafter, tasisulam) is a novel anticancer agent that induces apoptosis through the intrinsic pathway and has antiangiogenic activity in preclinical models. Tasisulam demonstrated activity across a broad range of tumors, including melanoma. The primary objective of this phase 2 study was to determine the objective response rate (ORR) in patients who had received 1 previous systemic chemotherapy for unresectable/metastatic melanoma; secondary objectives were to evaluate the clinical response rate (CRR), progression-free survival (PFS), overall survival (OS), duration of response, safety, and pharmacokinetics. METHODS: Tasisulam was administered intravenously on Day 1 of 21-day cycles according to a lean body weight-based dosing algorithm targeting a peak plasma concentration (C max ) of 420 lg/mL. RESULTS: In 68 enrolled patients, the median age was 59 years (range, 26-83 years). No patients had a complete response (CR), 8 patients had a partial response (PR), and 24 patients had stable disease (SD); the ORR (CR þ PR) was 11.8%, and the CRR (CR þ PR þ SD) was 47.1%. The median PFS was 2.6 months, and the median OS was 9.6 months. The predominant treatment-related grade 3/4 toxicity was thrombocytopenia (20.6% of patients). Tasisulam exhibited a biexponential disposition with a predicted distribution half-life of 0.3 hours to 2.8 hours and a median terminal elimination half-life of 10 days (consistent with the turnover of albumin), suggesting that tasisulam is very tightly bound to albumin. CONCLUSIONS: Tasisulam administered at a targeted C max of 420 lg/mL on Day 1 of 21-day cycles demonstrated activity and tolerable toxicity as second-line treatment in malignant melanoma. These results led to a registration trial in metastatic melanoma. Cancer 2011;117:4732-

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Discovery of Solid Tumor Active Agents Using a Soft-Agar-Colony-Formation Disk-Diffusion-Assay

Cited by 46 publications

References 6 publications

Superior Antitumor Activity of SAR3419 to Rituximab in Xenograft Models for Non-Hodgkin's Lymphoma

Superior Antitumor Activity of SAR3419 to Rituximab in Xenograft Models for Non-Hodgkin's Lymphoma

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

A phase 2 study of tasisulam sodium (LY573636 sodium) as second‐line treatment for patients with unresectable or metastatic melanoma

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