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Activity of batracylin (NSC-320846) against solid tumors of mice
P Mucci-LoRusso1, L Polin, M C Bissery
1Department of Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201.
Abstract:
Batracylin (NSC 320846) is a water insoluble, solid tumor active compound discovered by the Development Therapeutics Program of the National Cancer Institute (NCI). In vivo, the NCI found this compound to be highly active [median treated tumor mass/median control tumor mass (T/C) = 0 to 20%] both orally and intraperitoneally against colon 38. In a disk diffusion, soft agar colony formation assay (500 ug/disk), we found solid tumor selectively (compared to leukemia L1210) against colon adenocarcinoma 38 (0-170 zu:L1210 leukemia; greater than 950 zu:C8), colon adenocarcinoma 9 (0-170 zu:L1210; greater than 950 zu:C9), colon adenocarcinoma 7/A (0-170 zu:L1210; 250-400 zu:C7), and pancreas ductal carcinoma 03 (0-170 zu:L1210; greater than 950 zu:Panc 03 (200 zone units [zu] = 6.5 mm zone of inhibition of cultured tumor colonies from drug disk). In vivo we have tested batracylin against mammary adenocarcinoma 16/C, colon 9, colon 38, colon 51, Panc 03, and hepatoma 129. Upon oral administration, batracylin was effective against colon 9 (T/C = 2.4%) and marginally active against colon 38 (T/C = 39%). Batracylin was orally ineffective against Panc 03 (T/C greater than 100%), colon #51 (T/C = 77%) and hepatoma 129 (T/C greater than 100%). Upon subcutaneous administration, batracylin was effective against colon #9 (T/C = 0%), and Panc 03 (T/C = 15%) but ineffective against mammary 16/C (T/C greater than 100%). At efficacious doses, delayed neurotoxicity, hepatic toxicity and a significant host weight loss was noted (with slow recovery). Both our in vitro data and the NCI in vivo data confirm its scant activity against L1210 (%ILS = 8 to 16%). Although showing activity against selected murine solid tumors, it lacked curative potential with early stage disease [C38, C9, Panc 03] and has shown relative inactivity in vitro against human solid tumor cell lines (H-125, CX-1, HCT-8, HCT-116). Batracylin has entered large animal toxicology trials at the NCI, anticipating phase I clinical evaluation.
Insights
Batracylin, a compound active against solid tumors, showed effectiveness in vivo against murine colon and pancreas cancers. However, it demonstrated limited efficacy against human cell lines and exhibited toxicity, hindering its curative potential.
Area of Science:
- Oncology
- Pharmacology
- Drug Discovery
Background:
- Batracylin (NSC 320846) is a novel, water-insoluble compound identified by the National Cancer Institute (NCI).
- The compound exhibits activity against solid tumors, prompting further investigation into its therapeutic potential.
Purpose of the Study:
- To evaluate the in vitro and in vivo efficacy of Batracylin against various solid tumors.
- To assess the selectivity of Batracylin against specific cancer cell lines compared to leukemia.
- To determine the toxicity profile and curative potential of Batracylin in preclinical models.
Main Methods:
- In vivo studies using murine models (colon 38, colon 9, pancreas ductal carcinoma 03, etc.) with oral and intraperitoneal administration.
- In vitro assays including disk diffusion and soft agar colony formation to assess tumor selectivity.
- Evaluation of Batracylin's activity against human solid tumor cell lines (H-125, CX-1, HCT-8, HCT-116).
Main Results:
- Batracylin demonstrated significant in vivo activity against colon 9 (T/C = 0%) and pancreas ductal carcinoma 03 (T/C = 15%) upon subcutaneous administration.
- Oral administration showed effectiveness against colon 9 (T/C = 2.4%) but was marginally active against colon 38 (T/C = 39%).
- The compound exhibited limited activity against L1210 leukemia and showed relative inactivity against tested human solid tumor cell lines, alongside noted neurotoxicity and hepatic toxicity.
Conclusions:
- Batracylin shows selective activity against certain murine solid tumors but lacks curative potential in early-stage disease.
- Observed toxicities, including neurotoxicity and host weight loss, warrant careful consideration for clinical development.
- Further large animal toxicology trials are underway in anticipation of Phase I clinical evaluation.