Photodynamic Therapy with Motexafin Lutetium for Rectal Cancer

A Preclinical Model in the Dog

H. M. Ross, J. A. Smelstoys, G. J. Davis, Amy Kapatkin, F. Del Piero, E. Reineke, H. Wang, T. C. Zhu, T. M. Busch, A. G. Yodh, S. M. Hahn

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Purpose: Local recurrence of rectal cancer remains a significant clinical problem despite multi-modality therapy. Photodynamic Therapy (PDT) is a cancer treatment which generates tumor kill through the production of singlet oxygen in cells containing a photosensitizing drug when exposed to laser light of a specific wavelength. PDT is a promising modality for prevention of local recurrence of rectal cancer for several reasons: tumor cells may selectively retain photosensitizer at higher levels than normal tissues, the pelvis after mesorectal excision is a fixed space amenable to intra-operative illumination, and PDT can generate toxicity in tissues up to 1 cm thick. This study evaluated the safety, tissue penetration of 730 nm light, normal tissue toxicity and surgical outcome in a dog model of rectal resection after motexafin lutetium-mediated photodynamic therapy. Methods: Ten mixed breed dogs were used. Eight dogs underwent proctectomy and low rectal end to end stapled anastomosis. Six dogs received the photosensitizing agent motexafin lutetium (MLu, Pharmacyclics, Inc., Sunnyvale, CA) of 2 mg/kg preoperatively and underwent subsequent pelvic illumination of the transected distal rectum of 730 nm light with light doses ranging from 0.5 J/cm2 to 10 J/cm2 three hours after drug delivery. Two dogs received light, but no drug, and underwent proctectomy and low-rectal stapled anastomosis. Two dogs underwent midline laparotomy and pelvic illumination. Light penetration in tissues was determined for small bowel, rectum, pelvic sidewall, and skin. Clinical outcomes were recorded. Animals were sacrificed at 14 days and histological evaluation was performed. Results: All dogs recovered uneventfully. No dog suffered an anastomotic leak. Severe tissue toxicity was not seen. Histological findings at necropsy revealed mild enteritis in all dogs. The excitation light penetration depths were 0.46 ± 0.18, 0.46 ± 0.15, and 0.69 ± 0.39 cm, respectively, for rectum, small bowel, and peritoneum in dogs that had received MLu. For control dogs without photosensitizer MLu, the optical penetration depths were longer: 0.92 ± 0.63, 0.67 ± 0.10, and 1.1 ± 0.80 cm for rectum, small bowel, and peritoneum, respectively. Conclusion: Low rectal stapled anastomosis is safe when performed with MLu-mediated pelvic PDT in a dog model. Significant tissue penetration of 730 nm light into the rectum and pelvic sidewall was revealed without generation of significant toxicity or histological sequelae. Penetration depths of 730 nm light in pelvic tissue suggest that microscopic residual disease of less than 5 mm are likely to be treated adequately with MLu-mediated PDT. This approach merits further investigation as an adjuvant to total mesorectal excision and chemoradiation for rectal cancer.

Original languageEnglish (US)
Pages (from-to)323-330
Number of pages8
JournalJournal of Surgical Research
Volume135
Issue number2
DOIs
StatePublished - Oct 2006
Externally publishedYes

Fingerprint

Photochemotherapy
Rectal Neoplasms
Dogs
Light
Rectum
Photosensitizing Agents
Lighting
Peritoneum
motexafin lutetium
Pharmaceutical Preparations
Recurrence
Neoplasms
Singlet Oxygen
Anastomotic Leak
Enteritis
Pelvis
Laparotomy
Lasers

Keywords

  • adjuvant therapy
  • experimental surgery
  • photodynamic therapy
  • rectal cancer
  • recurrant rectal cancer
  • surgery

ASJC Scopus subject areas

  • Surgery

Cite this

Ross, H. M., Smelstoys, J. A., Davis, G. J., Kapatkin, A., Del Piero, F., Reineke, E., ... Hahn, S. M. (2006). Photodynamic Therapy with Motexafin Lutetium for Rectal Cancer: A Preclinical Model in the Dog. Journal of Surgical Research, 135(2), 323-330. https://doi.org/10.1016/j.jss.2006.01.020

Photodynamic Therapy with Motexafin Lutetium for Rectal Cancer : A Preclinical Model in the Dog. / Ross, H. M.; Smelstoys, J. A.; Davis, G. J.; Kapatkin, Amy; Del Piero, F.; Reineke, E.; Wang, H.; Zhu, T. C.; Busch, T. M.; Yodh, A. G.; Hahn, S. M.

In: Journal of Surgical Research, Vol. 135, No. 2, 10.2006, p. 323-330.

Research output: Contribution to journalArticle

Ross, HM, Smelstoys, JA, Davis, GJ, Kapatkin, A, Del Piero, F, Reineke, E, Wang, H, Zhu, TC, Busch, TM, Yodh, AG & Hahn, SM 2006, 'Photodynamic Therapy with Motexafin Lutetium for Rectal Cancer: A Preclinical Model in the Dog', Journal of Surgical Research, vol. 135, no. 2, pp. 323-330. https://doi.org/10.1016/j.jss.2006.01.020
Ross, H. M. ; Smelstoys, J. A. ; Davis, G. J. ; Kapatkin, Amy ; Del Piero, F. ; Reineke, E. ; Wang, H. ; Zhu, T. C. ; Busch, T. M. ; Yodh, A. G. ; Hahn, S. M. / Photodynamic Therapy with Motexafin Lutetium for Rectal Cancer : A Preclinical Model in the Dog. In: Journal of Surgical Research. 2006 ; Vol. 135, No. 2. pp. 323-330.
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abstract = "Purpose: Local recurrence of rectal cancer remains a significant clinical problem despite multi-modality therapy. Photodynamic Therapy (PDT) is a cancer treatment which generates tumor kill through the production of singlet oxygen in cells containing a photosensitizing drug when exposed to laser light of a specific wavelength. PDT is a promising modality for prevention of local recurrence of rectal cancer for several reasons: tumor cells may selectively retain photosensitizer at higher levels than normal tissues, the pelvis after mesorectal excision is a fixed space amenable to intra-operative illumination, and PDT can generate toxicity in tissues up to 1 cm thick. This study evaluated the safety, tissue penetration of 730 nm light, normal tissue toxicity and surgical outcome in a dog model of rectal resection after motexafin lutetium-mediated photodynamic therapy. Methods: Ten mixed breed dogs were used. Eight dogs underwent proctectomy and low rectal end to end stapled anastomosis. Six dogs received the photosensitizing agent motexafin lutetium (MLu, Pharmacyclics, Inc., Sunnyvale, CA) of 2 mg/kg preoperatively and underwent subsequent pelvic illumination of the transected distal rectum of 730 nm light with light doses ranging from 0.5 J/cm2 to 10 J/cm2 three hours after drug delivery. Two dogs received light, but no drug, and underwent proctectomy and low-rectal stapled anastomosis. Two dogs underwent midline laparotomy and pelvic illumination. Light penetration in tissues was determined for small bowel, rectum, pelvic sidewall, and skin. Clinical outcomes were recorded. Animals were sacrificed at 14 days and histological evaluation was performed. Results: All dogs recovered uneventfully. No dog suffered an anastomotic leak. Severe tissue toxicity was not seen. Histological findings at necropsy revealed mild enteritis in all dogs. The excitation light penetration depths were 0.46 ± 0.18, 0.46 ± 0.15, and 0.69 ± 0.39 cm, respectively, for rectum, small bowel, and peritoneum in dogs that had received MLu. For control dogs without photosensitizer MLu, the optical penetration depths were longer: 0.92 ± 0.63, 0.67 ± 0.10, and 1.1 ± 0.80 cm for rectum, small bowel, and peritoneum, respectively. Conclusion: Low rectal stapled anastomosis is safe when performed with MLu-mediated pelvic PDT in a dog model. Significant tissue penetration of 730 nm light into the rectum and pelvic sidewall was revealed without generation of significant toxicity or histological sequelae. Penetration depths of 730 nm light in pelvic tissue suggest that microscopic residual disease of less than 5 mm are likely to be treated adequately with MLu-mediated PDT. This approach merits further investigation as an adjuvant to total mesorectal excision and chemoradiation for rectal cancer.",
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author = "Ross, {H. M.} and Smelstoys, {J. A.} and Davis, {G. J.} and Amy Kapatkin and {Del Piero}, F. and E. Reineke and H. Wang and Zhu, {T. C.} and Busch, {T. M.} and Yodh, {A. G.} and Hahn, {S. M.}",
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T1 - Photodynamic Therapy with Motexafin Lutetium for Rectal Cancer

T2 - A Preclinical Model in the Dog

AU - Ross, H. M.

AU - Smelstoys, J. A.

AU - Davis, G. J.

AU - Kapatkin, Amy

AU - Del Piero, F.

AU - Reineke, E.

AU - Wang, H.

AU - Zhu, T. C.

AU - Busch, T. M.

AU - Yodh, A. G.

AU - Hahn, S. M.

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N2 - Purpose: Local recurrence of rectal cancer remains a significant clinical problem despite multi-modality therapy. Photodynamic Therapy (PDT) is a cancer treatment which generates tumor kill through the production of singlet oxygen in cells containing a photosensitizing drug when exposed to laser light of a specific wavelength. PDT is a promising modality for prevention of local recurrence of rectal cancer for several reasons: tumor cells may selectively retain photosensitizer at higher levels than normal tissues, the pelvis after mesorectal excision is a fixed space amenable to intra-operative illumination, and PDT can generate toxicity in tissues up to 1 cm thick. This study evaluated the safety, tissue penetration of 730 nm light, normal tissue toxicity and surgical outcome in a dog model of rectal resection after motexafin lutetium-mediated photodynamic therapy. Methods: Ten mixed breed dogs were used. Eight dogs underwent proctectomy and low rectal end to end stapled anastomosis. Six dogs received the photosensitizing agent motexafin lutetium (MLu, Pharmacyclics, Inc., Sunnyvale, CA) of 2 mg/kg preoperatively and underwent subsequent pelvic illumination of the transected distal rectum of 730 nm light with light doses ranging from 0.5 J/cm2 to 10 J/cm2 three hours after drug delivery. Two dogs received light, but no drug, and underwent proctectomy and low-rectal stapled anastomosis. Two dogs underwent midline laparotomy and pelvic illumination. Light penetration in tissues was determined for small bowel, rectum, pelvic sidewall, and skin. Clinical outcomes were recorded. Animals were sacrificed at 14 days and histological evaluation was performed. Results: All dogs recovered uneventfully. No dog suffered an anastomotic leak. Severe tissue toxicity was not seen. Histological findings at necropsy revealed mild enteritis in all dogs. The excitation light penetration depths were 0.46 ± 0.18, 0.46 ± 0.15, and 0.69 ± 0.39 cm, respectively, for rectum, small bowel, and peritoneum in dogs that had received MLu. For control dogs without photosensitizer MLu, the optical penetration depths were longer: 0.92 ± 0.63, 0.67 ± 0.10, and 1.1 ± 0.80 cm for rectum, small bowel, and peritoneum, respectively. Conclusion: Low rectal stapled anastomosis is safe when performed with MLu-mediated pelvic PDT in a dog model. Significant tissue penetration of 730 nm light into the rectum and pelvic sidewall was revealed without generation of significant toxicity or histological sequelae. Penetration depths of 730 nm light in pelvic tissue suggest that microscopic residual disease of less than 5 mm are likely to be treated adequately with MLu-mediated PDT. This approach merits further investigation as an adjuvant to total mesorectal excision and chemoradiation for rectal cancer.

AB - Purpose: Local recurrence of rectal cancer remains a significant clinical problem despite multi-modality therapy. Photodynamic Therapy (PDT) is a cancer treatment which generates tumor kill through the production of singlet oxygen in cells containing a photosensitizing drug when exposed to laser light of a specific wavelength. PDT is a promising modality for prevention of local recurrence of rectal cancer for several reasons: tumor cells may selectively retain photosensitizer at higher levels than normal tissues, the pelvis after mesorectal excision is a fixed space amenable to intra-operative illumination, and PDT can generate toxicity in tissues up to 1 cm thick. This study evaluated the safety, tissue penetration of 730 nm light, normal tissue toxicity and surgical outcome in a dog model of rectal resection after motexafin lutetium-mediated photodynamic therapy. Methods: Ten mixed breed dogs were used. Eight dogs underwent proctectomy and low rectal end to end stapled anastomosis. Six dogs received the photosensitizing agent motexafin lutetium (MLu, Pharmacyclics, Inc., Sunnyvale, CA) of 2 mg/kg preoperatively and underwent subsequent pelvic illumination of the transected distal rectum of 730 nm light with light doses ranging from 0.5 J/cm2 to 10 J/cm2 three hours after drug delivery. Two dogs received light, but no drug, and underwent proctectomy and low-rectal stapled anastomosis. Two dogs underwent midline laparotomy and pelvic illumination. Light penetration in tissues was determined for small bowel, rectum, pelvic sidewall, and skin. Clinical outcomes were recorded. Animals were sacrificed at 14 days and histological evaluation was performed. Results: All dogs recovered uneventfully. No dog suffered an anastomotic leak. Severe tissue toxicity was not seen. Histological findings at necropsy revealed mild enteritis in all dogs. The excitation light penetration depths were 0.46 ± 0.18, 0.46 ± 0.15, and 0.69 ± 0.39 cm, respectively, for rectum, small bowel, and peritoneum in dogs that had received MLu. For control dogs without photosensitizer MLu, the optical penetration depths were longer: 0.92 ± 0.63, 0.67 ± 0.10, and 1.1 ± 0.80 cm for rectum, small bowel, and peritoneum, respectively. Conclusion: Low rectal stapled anastomosis is safe when performed with MLu-mediated pelvic PDT in a dog model. Significant tissue penetration of 730 nm light into the rectum and pelvic sidewall was revealed without generation of significant toxicity or histological sequelae. Penetration depths of 730 nm light in pelvic tissue suggest that microscopic residual disease of less than 5 mm are likely to be treated adequately with MLu-mediated PDT. This approach merits further investigation as an adjuvant to total mesorectal excision and chemoradiation for rectal cancer.

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KW - experimental surgery

KW - photodynamic therapy

KW - rectal cancer

KW - recurrant rectal cancer

KW - surgery

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