Halina Kusnierczyk

Synergistic antitumour effects of chemo-immunotherapy with an oxazaphosphorine drug and IL-2-secreting cells in a mouse colon cancer model

The therapeutic efficacies of two chemical agents—cyclophosphamide (CY) and compound CBM-11—were compared in a chemo-immunotherapy protocol combining a single injection of a cytotoxic agent with a series of weekly peritumoural (p.t.) administrations of nontumourigenic plasmocytoma cells engineered to produce interleukin-2 (IL-2). Compound CBM-11, an optically active S(−) isomeric form of a bromine-substituted analogue of ifosfamide, is currently used in Phase I clinical trials in Poland. The treatment was applied to mice bearing well-established subcutaneous (s.c.) MC-38 colon tumours. Single intraperitoneal injection of 200 mg/kg of CY or of an equitoxic dose of 140 mg/kg of CBM-11 alone resulted in a tumour growth delay (TGD) of 10–13 and 17–21 d, respectively. This effect was accompanied by an increase in life-span (ILS) of at most 42 and 62% over control. Complete responses (CR) were not observed. Combination of CY or CBM-11 with 6–7 p.t. injections of IL-2-secreting cells resulted in potentiation of the therapeutic effects: TGD and ILS values were considerably increased and long-lasting CRs were observed. The overall incidence of CR after combined treatment was ca 16% and 42% for CY and CBM-11, respectively (P=0.049). A specific anti-MC-38 immunity was induced by the treatment, as verified by rechallenge of cured mice with MC-38 tumour cells 3–4 months post therapy cessation. Our results indicate that tumour destruction by chemotherapy (even if not complete) and prolonged local delivery of IL-2 secreted by allogeneic cells of an easy to culture line are sufficient to secure long-lasting specific antitumour immunity in cured mice.

Synthesis and antitumour activity of stereoisomers of 4-hydroperoxy derivatives of ifosfamide and its bromo analogue

Racemic mixtures and laevorotatory enantiomers of cis- and trans-4-hydroperoxyifosfamide and 4-hydroperoxybromofosfamide possess high antitumour activity both in vitro and in vivo. However, no major differences in biological activity were observed among these stereoisomers.

Synthesis, in vitro metabolic studies, and antitumour activity of methyl analogues of ifosfamide

Synthesis of 2‐chloro‐1,1‐dimethylethyl and 2‐chloro‐2,2‐dimethylethyl analogues of ifosfamide was performed via aziridine intermediate. In vitro metabolic activation showed that both compounds are metabolised at a rate similar to the parent drug. However, their anticancer activity against L1210 leukaemia in mice was lower as compared with ifosfamide. The reduction of antitumour efficiency of examined analogues is probably caused by a lower ability to cross‐link DNA by their final, active metabolites.