Enhancement of photodynamic therapy by mitomycin C: a preclinical and clinical study

Abstract

Summary Photodynamic therapy (PDT) using Photofrin was used in combination with a hypoxic toxin (mitomycin C, MMC) to treat four patients with recurrent skin metastasis of a mammary carcinoma. In precinical experiments an additive effect was found for the combination of MMC and PDT for treating subcutaneous RIFI tumours in mice. When interstitial PDT was combined with a low dose of MMC (administered 15 min before illumination), the Photofrin dose or light dose could be reduced by a factor of 2 in order to obtain equivalent cure rate or growth delay. In the clinical pilot study, a low dose of Photfrin (0.75 mg kg-') was used for PDT alone (superficial illumination) or combined with low-dose MMC (5 mg m-2). Different tumour areas were illuminated with or without a preceding infusion of MMC. Both tumour response and skin photosensitivity were scored. After 8-12 weeks of treatment, tumour cure could be achieved by administering light doses > 150 J cm-2 for PDT alone and similar effects were obtained when light doses of 75-87.5 J cm-2 were given after infusion with MMC. In all cases necrotic tissue of both tumour and surrounding skin was observed, which lasted for a mean of 5 months (range 2-20 months). Skin phototoxicity, tested by using a standardised illumination of skin patches on the back, lasted maximally 3 weeks. Three main conclusions could be drawn from these studies: (1) The enhanced effects of the combination of PDT and MMC observed in mouse tumours can be extrapolated to patients with mammary skin metastasis. (2) The combination of PDT and hypoxic toxins facilitates treatment by permitting lower doses of photosensitiser to be used (thereby reducing skin phototoxicity) or lower light doses (thereby reducing illumination times and allowing the possibility to treat larger tumour areas). (3) Restoration of skin after PDT in previously treated tumour areas (chemotherapy, radiation therapy and surgery) is very slow.

Effect of photodynamic therapy in combination with mitomycin C on a mitomycin-resistant bladder cancer cell line

“…The same authors have also treated four patients with breast metastases to the skin. They were able to achieve similar responses in those tumours treated with MMC followed by photodynamic therapy, compared with tumours treated with photodynamic therapy alone but using twice the light dose (Baas et al, 1996).…”

Effect of photodynamic therapy in combination with ionizing radiation on human squamous cell carcinoma cell lines of the head and neck

“…These marked fluctuations in PDT sensitivity with growth rate may account for the wide scatter observed in our measurements of clonogenic cell survival following PDT. Mitomycin C has been demonstrated to potentiate photodynamic therapy both at the cellular level (Ma et al, 1992a(Ma et al, , 1993aDatta et al, 1997) and in vivo (Baas et al, 1994(Baas et al, , 1996. This potentiation of PDT is associated with a mitomycin-C induced cell cycle arrest in late S-phase/G2 (Ma et al, 1992b).…”

The influence of hypoxia and pH on aminolaevulinic acid-induced photodynamic therapy in bladder cancer cells in vitro

“…Hypoxic radiosensitizers, such as mizonidazole, which substitutes for oxygen in accepting radicals, have enhanced cancer cure rates (Hirsch et al, 1987). Concommitant use of chemotherapeutic agents that target hypoxic cells, such as mitomycin C, which is selectively metabolized to toxic intermediates by hypoxic cells, have also shown promise (Baas et al, 1996). Another potent bioreductive drug, tirapazamine (SR 4233), is currently undergoing clinical trials and may be used as an adjunct to PDT, although initial in vivo studies have only shown a slight improvement in survival with this agent (Baas et al, 1993).…”