Table 1.

Summary of main findings of in vitro selection of resistance to antimalarials in P. falciparum strains

Drugs	Strains (drug resistance profilea)	Ric (IC50)	Ratio of HDCd per IC50 after drug pressure	Time required to select resistance (months)	Stability: period of drug-free culture (months)	Work carried out on parasite lines: main finding	Ref.
CQ	FCR3 (CQ and CG resistant)	NM	NM	4	1	NM	10
	FAC8 (CQ resistant)	2.34 (83 ng/mL)	1.23	NM	1	deamplification of pfmdr1 in association with CQ resistance	34
	HB3 (PM resistant)	1.64 (28 ng/mL)	1.74	30	NM	DNA amplification in chromosomes 3 and 12; deamplification in chromosome 3 after drug removal	39
	106/01 (CQ susceptible)b	12 (37 nM)	0.23	2	NM	evidence that the presence of pre-existing mutations in pfcrt lead to a rapid selection of the key 76 mutation	38
MFQ	FCK (CQ resistant)	16 (8 nmol/L)	0.5	3	NM	NM	27
	Smith (CQ, PM and SD resistant)	3.4 (3.5 µg/L)				inverse relationship between MFQ and CQ	28
	Camp (CQ susceptible)	2.4 (4.9–12 µg/L)	1.66	>1e	6 and cryopreservation
	W2 (CQ, PM and SD resistant)	4.6 (4.5 nM)	1.93	22.4	12	1. inverse relationship between CQ and MFQ activity	21
						2. identification of pfmdr1 as MFQ resistance marker
	K1 (CQ, PM and SD resistant)	4.07 (22.4 ng/mL)	0.8	NM	NM	1. MFQ resistance associated with pfmdr1 overamplification	29
	W2mef (CQ, PM, SD and MFQ resistant)	1.41 (58.88 ng/mL)	1.08	NM	NM	2. evidence of inverse relationship with CQ
	W2mef (CQ, PM, SD and MFQ resistant)	1.07 (15.2 ng/mL)	148.1	18	NM	evidence of cross-resistance with HFT and QN and inverse relationship with CQ	26
HFT	T9.96 (CQ susceptible)	3.3 (6.6–22 nM)	0.45	6	6 and cryopreservation	cross-resistance with QN but inverse relationship with CQ	71
	K1 (CQ and SD resistant)	9 (2.2 nM)	0.4	2
PM	FCR3	NM (15 nM)	NM	7		DNA amplification (chromosome containing dhfrf)	40
5FO	W2	100 (2 nM)	1	2	NM	evidence that resistance emerges quicker in already resistant strains	63
	FCR3	NM	1	2	NM
ATV	W2	30 (3 nM)	1.1	2	NM	evidence that resistance emerges quicker in already resistant strains	63
	K1	837 (13.6 nM)	1.6	NM	<3	evidence that mutations in cytochrome b are associated with ATV resistance	46
BMS-3888891	Dd2 (CQ, QN, PM and SD resistant)	12 (10 nM)	NM	2.66	NM	evidence that resistance is associated with point mutation in protein farnesyl transferase	51
N-89	FCR3	10 (25 nM)	NM	24	NM	no cross-resistance between the endoperoxides N-89 and artemisinin	70
AZ	Dd2	15.3 (124 nM)	NM	0.7	NM	AZ resistance is associated with point mutation in ribosomal protein L4 (pfRpL4)	59
	7G8 (CQ and PM resistant)	17.5 (228 nM)	NM	0.7	NM

CQ, chloroquine; CG, cycloguanil; SD, sulfadoxine; PM, pyrimethamine; HFT, halofantrine; MFQ, mefloquine; ATV, atovaquone; 5FO, 5-fluoro-orotate; AZ, azithromycin; QN, quinine; NM, not mentioned.

^aInformation on resistance phenotype was presented in the references listed in the table and in Nkrumah et al.⁷¹

^bThis strain is CQ susceptible; it has mutations in five codons of pfcrt, but not at codon 76. After drug pressure, two parasite lines were obtained: one with pfcrt-76 asparagine and a second with pfcrt-76 isoleucine, with IC₅₀ values of 302.2 and 443.1 nM, respectively. We used the highest IC₅₀ (443.1 nM) in the table. The normal mutant in CQ resistance is pfcrt-76 threonine.

^cRi, resistance index: the ratio of the IC₅₀ of the selected parasite line to the IC₅₀ of the parent strain (before drug pressure).

^dHDC, highest drug concentration tested, in which the parasite lines could grow after drug pressure.

^eExact time period was not given.

^fdhfr, dihydrofolate reductase gene.