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tic armamentarium, their use, in our opinion, cannot be dis-couraged on the grounds of carcinogenicity.

Aberdeen-Dundee Medicines Evaluationand Monitoring Group,

Ninewells Hospital,Dundee DD2 1UB

L. J. CHRISTOPHERJ. CROOKSD. MOIRR. D. WEIR

MEMBRANE MANIPULATION AND CANCERCHEMOTHERAPY

SIR,-In 1970 Van Breeman suggested that malignant cellmembranes might be sensitised to the lethal effect of the

polyene antibiotic amphotericin B by first exposing cells to

high cholesterol concentrations via local perfusion, intra-venous administration, or diet.’ Since new membranes ofcancer cells are formed rapidly and since their composition ismore dependent on immediate substrate concentrations thanare membranes of slower-growing normal cells, this couldserve as a basis for differential uptake of such ambient sub-stances.

L1210 murine leukzmia cells grown in culture medium con-taining ergosterol (a sterol structurally related to cholesteroland found in fungal cell membranes) sustain membranedamage, growth inhibition, and cell death when exposed toamphotericin B.1 Since some types of rapidly dividing cellsmore efficiently take up and are more sensitive to certain

chemotherapeutic drugs,’ we examined the effect of cell-pro-liferation rate on amphotericin-B sensitivity. Preliminary datasuggest that populations of L1210 cells first grown in ergos-terol and harvested in logarithmic phase are more sensitive to

1. Van Breeman, C. Lancet, 1970, ii, 895.2. Schiffman, F. J., Fisher, J. M., Rabinovitz, M. Biochem. Pharmac. (in the

press).3. Goldenberg, G. J., Lyons, R. M., Lipp, J. A., Vanstone, C. A. Cancer Res.

1971, 31, 1616.

AMP-B Concentration in /-I9/mlEffect of cell-proliferation rate on amphotericin-B sensitivity.

the action of amphotericin B than are comparable cells in

stationary phase (see figure). Cell survival was assessed bycounting the colonies derived from cells which were

drug-treated, then washed and incubated in an agar-mediummixture for two weeks at 37°C.These findings show that membrane manipulation of cell

types may have a role in the development of cancer chemo-therapeutic agents.

Laboratory of Medicinal Chemistryand Biology

National Cancer Institute,Bethesda, Maryland 20014, U.S.A.

FRED J. SCHIFFMAN

DAVID T. VISTICA

INTENSIVE CANCER CHEMOTHERAPY

SIR,-Not only do we disagree with Price and Hill’ whoaccuse us of "apparent misinterpretation of the relevance ofthe experimental model of Bruce and his colleagues" but alsowe dispute their claim of having "outlined the real clinical im-portance" of this model.The Bruce model would clearly predict (as Price and Hill

state) that increased tumour-cell kill should be observed withhigher doses of cell-cycle-specific agents, such as cyclophospha-mide. Unfortunately, although well documented in animalmodels, the data in man do not as yet support this view. Stu-dies both in Burkitt’s lymphoma3 and ovarian cancer havefailed to show a real advantage for intensive cyclophosphamidetreatment. In a controlled trial in ovarian cancer, high-dosecyclophosphamide treatment was no more clinically effectivethan low-dose alkylating agent therapy, although it was sub-

stantially more toxic."Unfortunately three of the six references cited by Price and

Hill supporting their claim of "reduced marrow toxicity with-out loss of anti-tumour effect" are unavailable to us-one setof unpublished results, one personal communication, and onepaper in the press. Of the other three papers cited none is acontrolled clinical trial in which their complex multiple-drugregimen has been tested against simpler combinations. We feelthat their claim that "all of the predictions from this modelwhen tested clinically have proved relevant" is premature.We entirely agree that cancer chemotherapy does not have

to be toxic to be effective and we were surprised that Price andHill felt our paper supported the opposite view.Are cell-kinetic data relevant in the design of chemotherapy

schedules? This whole area has been comprehensively reviewedby van Putten,’ who pointed out that in animal models, theplateau phase of the dose-response curve of phase-specificagents was usually reached only at toxic (often lethal) doses.This obviously lessens the clinical importance of the distinctionbetween phase specific and cycle specific agents since, in man,all of these drugs would be given at far lower dosages thanused in the animal models-i.e., at doses in which a clearlinear dose-response relationship still applied for both types ofagent.,In discussing the limitation of the Bruce model, vanPutten pointed out several important differences between thekinetics of murine and human tumours (we were criticised byPrice and Hill for doing the same). As van Putten points out:

"a close comparison of cell kinetic data has indicated that the situ-ation in man is very different from the situation in the model of Bruceet al.... the doubling times of human primary tumours are withoutexception very much longer than that of the model lymphoma used ...but it seems certain that in human tumours the proliferation rate isonly rarely higher than that observed in the most critical normalhuman tissue ... thus a mode of chemotherapy based solely on thedifferential proliferation rate of normal and malignant cells would notbe very successful ... fortunately there is evidence from many sources

1. Price, L. A., Hill, B. T. Lancet, 1976, ii, 1195.2. Tattersall, M. H. N., Tobias, J. S. ibid. p. 1071.3. Durodola, J. I. Eur. J. Cancer, 1976, 12, 425.4. Young, R C., Canellos, G. P., Chabner, B. A., Schein, P. S., De Vita, V. T.

Gynec. Oncol. 1974, 2, 489.5. van Putten, L. M. Cell Tissue Kinet, 1974, 7, 493.