Summary.-The in vivo biological activity of various fractions and components of haematoporphyrin derivative (HpD) have been determined by measuring the depth of necrosis of implanted tumours in mice exposed to light after the administration of standard doses of porphyrins dissolved in alkali.In this assay, haematoporphyrin, hydroxyethylvinyldeuteroporphyrin and protoporphyrin are inactive, but the mono-and di-acetates of haematoporphyrin (which are major components of HpD) and acetoxyethylvinyldeuteroporphyrin are Active.However, the situation appears to be more complex than this. The normal method for preparing HpD for injection involves an alkali treatment which causes hydrolysis and elimination of the acetoxy functions, and the only recognized products (haematoporphyrin, hydroxyethylvinyldeuteroporphyrin and protoporphyrin) are inactive in the in vivo assay. It is concluded that the active component here is a porphyrin, possibly a dimer or oligomer, which is retained on the column during the normal separation by HPLC. This conclusion is supported by the observations that (i) the crude material obtained from the spent column is active without further alkali treatment, and (ii) activity develops over 30 min, when HpD or the mono-or diacetates of haematoporphyrin are treated with sodium bicarbonate in aqueous DMSO.The advantages of working with a pure substance (e.g. haematoporphyrin diacetate) rather than a mixture (HpD) are stressed.
Abstract— Nanosecond laser flash photolysis and pulse radiolysis have been used to generate and characterise the triplet state, and semioxidised and semireduced radicals of haematoporphyrin, and three 0‐acyl compounds derived from it (the monoacetate, the diacetate and the disuccinate).
After 347 nm irradiation in water containing 2% Triton X‐100, haematoporphyrin forms the triplet state (φT= 0.92) and photoionises monophotonically (φI= 0.03). For the O‐acyl derivatives, φT approaches unity and photoionisation is reduced. In acetone the triplet yield of all four compounds are close to unity. The difference and corrected spectra for the triplet species are presented and decay rates (k1˜104s‐1) and oxygen quenching constants (kQ˜1.5times109M‐1s‐1) for the triplet state have been measured. The difference and corrected spectra for the semi‐reduced species in methanol and semi‐oxidised species in aqueous Triton X‐100 are presented.
The photophysical characteristics in fluid solution of haematoporphyrin and its 0‐acyl derivatives are rather similar to those previously recorded for other photosensitising porphyrins.
A series of bis-daunomycin hydrazones were synthesised from diester diamide linking groups derived from alpha,omega-dicarboxylic acids. All members of the series bis-intercalated into DNA, as evidenced by doubling of the lengthening of rod-like DNA compared to daunomycin, and by a 1000-5000 fold slower dissociation from DNA than daunomycin under detergent sequestration conditions. The bis-hydrazones exhibited neighbour exclusion, and occupied 6 bp under saturating conditions of drug. A unique DNA sequence specificity was apparent from transcriptional footprinting of 100 bp of DNA, with the greatest preference for 5'-CACA sites.
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